Functional interaction of the DNA-binding transcription factor Sp1 through its DNA-binding domain with the histone chaperone TAF-I.

PubMed

Suzuki, Toru; Muto, Shinsuke; Miyamoto, Saku; Aizawa, Kenichi; Horikoshi, Masami; Nagai, Ryozo

2003-08-01

Transcription involves molecular interactions between general and regulatory transcription factors with further regulation by protein-protein interactions (e.g. transcriptional cofactors). Here we describe functional interaction between DNA-binding transcription factor and histone chaperone. Affinity purification of factors interacting with the DNA-binding domain of the transcription factor Sp1 showed Sp1 to interact with the histone chaperone TAF-I, both alpha and beta isoforms. This interaction was specific as Sp1 did not interact with another histone chaperone CIA nor did other tested DNA-binding regulatory factors (MyoD, NFkappaB, p53) interact with TAF-I. Interaction of Sp1 and TAF-I occurs both in vitro and in vivo. Interaction with TAF-I results in inhibition of DNA-binding, and also likely as a result of such, inhibition of promoter activation by Sp1. Collectively, we describe interaction between DNA-binding transcription factor and histone chaperone which results in negative regulation of the former. This novel regulatory interaction advances our understanding of the mechanisms of eukaryotic transcription through DNA-binding regulatory transcription factors by protein-protein interactions, and also shows the DNA-binding domain to mediate important regulatory interactions.

Histone chaperones: an escort network regulating histone traffic.

PubMed

De Koning, Leanne; Corpet, Armelle; Haber, James E; Almouzni, Geneviève

2007-11-01

In eukaryotes, DNA is organized into chromatin in a dynamic manner that enables it to be accessed for processes such as transcription and repair. Histones, the chief protein component of chromatin, must be assembled, replaced or exchanged to preserve or change this organization according to cellular needs. Histone chaperones are key actors during histone metabolism. Here we classify known histone chaperones and discuss how they build a network to escort histone proteins. Molecular interactions with histones and their potential specificity or redundancy are also discussed in light of chaperone structural properties. The multiplicity of histone chaperone partners, including histone modifiers, nucleosome remodelers and cell-cycle regulators, is relevant to their coordination with key cellular processes. Given the current interest in chromatin as a source of epigenetic marks, we address the potential contributions of histone chaperones to epigenetic memory and genome stability.

Interferon regulatory factor 1 and histone H4 acetylation in systemic lupus erythematosus

PubMed Central

Leung, Yiu Tak; Shi, Lihua; Maurer, Kelly; Song, Li; Zhang, Zhe; Petri, Michelle; Sullivan, Kathleen E

2015-01-01

Histone acetylation modulates gene expression and has been described as increased in systemic lupus erythematosus (SLE). We investigated interferon regulatory factor 1 (IRF1) interactions that influence H4 acetylation (H4ac) in SLE. Intracellular flow cytometry for H4 acetylated lysine (K) 5, K8, K12, and K16 was performed. Histone acetylation was defined in monocytes and T cells from controls and SLE patients. RNA-Seq studies were performed on monocytes to look for an imbalance in histone acetyltransferases and histone deacetylase enzyme expression. Expression levels were validated using real-time quantitative RT-PCR. IRF1 induction of H4ac was evaluated using D54MG cells overexpressing IRF1. IRF1 protein interactions were studied using co-immunoprecipitation assays. IRF1-dependent recruitment of histone acetyltransferases to target genes was examined by ChIP assays using p300 antibody. Flow cytometry data showed significantly increased H4K5, H4K8, H4K12, and H4K16 acetylation in SLE monocytes. HDAC3 and HDAC11 gene expression were decreased in SLE monocytes. PCAF showed significantly higher gene expression in SLE than controls. IRF1-overexpressing D54MG cells were associated with significantly increased H4K5, H4K8, and H4K12 acetylation compared to vector-control D54MG cells both globally and at specific target genes. Co-immunoprecipitation studies using D54MG cells revealed IRF1 protein-protein interactions with PCAF, P300, CBP, GCN5, ATF2, and HDAC3. ChIP experiments demonstrated increased p300 recruitment to known IRF1 targets in D54MG cells overexpressing IRF1. In contrast, p300 binding to IRF1 targets decreased in D54MG cells with IRF1 knockdown. SLE appears to be associated with an imbalance in histone acetyltransferases and histone deacetylase enzymes favoring pathologic H4 acetylation. Furthermore, IRF1 directly interacts with chromatin modifying enzymes, supporting a model where recruitment to specific target genes is mediated in part by IRF1. PMID

Use of Polyamine Derivatives as Selective Histone Deacetylase Inhibitors

PubMed Central

Woster, Patrick M.

2014-01-01

Histone acetylation and deacetylation, mediated by histone acetyltransferase and the 11 isoforms of histone deacetylase, play an important role in gene expression. Histone deacetylase inhibitors have found utility in the treatment of cancer by promoting the reexpression of aberrantly silenced genes that code for tumor suppressor factors. It is unclear which of the 11 histone deacetylase isoforms are important in human cancer. We have designed a series of polyaminohydroxamic acid (PAHA) and polyaminobenzamide (PABA) histone deacetylase inhibitors that exhibit selectivity among four histone deacetylase isoforms. Although all of the active inhibitors promote reexpression of tumor suppressor factors, they produce variable cellular effects ranging from stimulation of growth to cytostasis and cytotoxicity. This chapter describes the procedures used to quantify the global and isoform-specific inhibition caused by these inhibitors, and techniques used to measure cellular effects such as reexpression of tumor suppressor proteins and hyperacetylation of histones H3 and H4. Procedures are also described to examine the ability of PAHAs and PABAs to utilize the polyamine transport system and to induce overexpression of the early apoptotic factor annexin A1. PMID:21318894

Occupational and non-occupational factors associated with work-related injuries among construction workers in the USA

PubMed Central

Dong, Xiuwen Sue; Wang, Xuanwen; Largay, Julie A.

2015-01-01

Background: Many factors contribute to occupational injuries. However, these factors have been compartmentalized and isolated in most studies. Objective: To examine the relationship between work-related injuries and multiple occupational and non-occupational factors among construction workers in the USA. Methods: Data from the 1988–2000 National Longitudinal Survey of Youth, 1979 cohort (N = 12,686) were analyzed. Job exposures and health behaviors were examined and used as independent variables in four multivariate logistic regression models to identify associations with occupational injuries. Results: After controlling for demographic variables, occupational injuries were 18% (95% CI: 1.04–1.34) more likely in construction than in non-construction. Blue-collar occupations, job physical efforts, multiple jobs, and long working hours accounted for the escalated risk in construction. Smoking, obesity/overweight, and cocaine use significantly increased the risk of work-related injury when demographics and occupational factors were held constant. Conclusions: Workplace injuries are better explained by simultaneously examining occupational and non-occupational characteristics. PMID:25816923

Histone Core Phosphorylation Regulates DNA Accessibility*

PubMed Central

Brehove, Matthew; Wang, Tao; North, Justin; Luo, Yi; Dreher, Sarah J.; Shimko, John C.; Ottesen, Jennifer J.; Luger, Karolin; Poirier, Michael G.

2015-01-01

Nucleosome unwrapping dynamics provide transient access to the complexes involved in DNA transcription, repair, and replication, whereas regulation of nucleosome unwrapping modulates occupancy of these complexes. Histone H3 is phosphorylated at tyrosine 41 (H3Y41ph) and threonine 45 (H3T45ph). H3Y41ph is implicated in regulating transcription, whereas H3T45ph is involved in DNA replication and apoptosis. These modifications are located in the DNA-histone interface near where the DNA exits the nucleosome, and are thus poised to disrupt DNA-histone interactions. However, the impact of histone phosphorylation on nucleosome unwrapping and accessibility is unknown. We find that the phosphorylation mimics H3Y41E and H3T45E, and the chemically correct modification, H3Y41ph, significantly increase nucleosome unwrapping. This enhances DNA accessibility to protein binding by 3-fold. H3K56 acetylation (H3K56ac) is also located in the same DNA-histone interface and increases DNA unwrapping. H3K56ac is implicated in transcription regulation, suggesting that H3Y41ph and H3K56ac could function together. We find that the combination of H3Y41ph with H3K56ac increases DNA accessibility by over an order of magnitude. These results suggest that phosphorylation within the nucleosome DNA entry-exit region increases access to DNA binding complexes and that the combination of phosphorylation with acetylation has the potential to significantly influence DNA accessibility to transcription regulatory complexes. PMID:26175159

Histone H3 and the histone acetyltransferase Hat1p contribute to DNA double-strand break repair.

PubMed

Qin, Song; Parthun, Mark R

2002-12-01

The modification of newly synthesized histones H3 and H4 by type B histone acetyltransferases has been proposed to play a role in the process of chromatin assembly. The type B histone acetyltransferase Hat1p and specific lysine residues in the histone H3 NH(2)-terminal tail (primarily lysine 14) are redundantly required for telomeric silencing. As many gene products, including other factors involved in chromatin assembly, have been found to participate in both telomeric silencing and DNA damage repair, we tested whether mutations in HAT1 and the histone H3 tail were also sensitive to DNA-damaging agents. Indeed, mutations both in specific lysine residues in the histone H3 tail and in HAT1 resulted in sensitivity to methyl methanesulfonate. The DNA damage sensitivity of the histone H3 and HAT1 mutants was specific for DNA double-strand breaks, as these mutants were sensitive to the induction of an exogenous restriction endonuclease, EcoRI, but not to UV irradiation. While histone H3 mutations had minor effects on nonhomologous end joining, the primary defect in the histone H3 and HAT1 mutants was in the recombinational repair of DNA double-strand breaks. Epistasis analysis indicates that the histone H3 and HAT1 mutants may influence DNA double-strand break repair through Asf1p-dependent chromatin assembly.

The histone shuffle: histone chaperones in an energetic dance

PubMed Central

Das, Chandrima; Tyler, Jessica K.; Churchill, Mair E.A.

2014-01-01

Our genetic information is tightly packaged into a rather ingenious nucleoprotein complex called chromatin in a manner that enables it to be rapidly accessed during genomic processes. Formation of the nucleosome, which is the fundamental unit of chromatin, occurs via a stepwise process that is reversed to enable the disassembly of nucleosomes. Histone chaperone proteins have prominent roles in facilitating these processes as well as in replacing old histones with new canonical histones or histone variants during the process of histone exchange. Recent structural, biophysical and biochemical studies have begun to shed light on the molecular mechanisms whereby histone chaperones promote chromatin assembly, disassembly and histone exchange to facilitate DNA replication, repair and transcription. PMID:20444609

A Qualitative Study on Organizational Factors Affecting Occupational Accidents.

PubMed

Eskandari, Davood; Jafari, Mohammad Javad; Mehrabi, Yadollah; Kian, Mostafa Pouya; Charkhand, Hossein; Mirghotbi, Mostafa

2017-03-01

Technical, human, operational and organizational factors have been influencing the sequence of occupational accidents. Among them, organizational factors play a major role in causing occupational accidents. The aim of this research was to understand the Iranian safety experts' experiences and perception of organizational factors. This qualitative study was conducted in 2015 by using the content analysis technique. Data were collected through semi-structured interviews with 17 safety experts working in Iranian universities and industries and analyzed with a conventional qualitative content analysis method using the MAXQDA software. Eleven organizational factors' sub-themes were identified: management commitment, management participation, employee involvement, communication, blame culture, education and training, job satisfaction, interpersonal relationship, supervision, continuous improvement, and reward system. The participants considered these factors as effective on occupational accidents. The mentioned 11 organizational factors are probably involved in occupational accidents in Iran. Naturally, improving organizational factors can increase the safety performance and reduce occupational accidents.

ATP-citrate lyase links cellular metabolism to histone acetylation.

PubMed

Wellen, Kathryn E; Hatzivassiliou, Georgia; Sachdeva, Uma M; Bui, Thi V; Cross, Justin R; Thompson, Craig B

2009-05-22

Histone acetylation in single-cell eukaryotes relies on acetyl coenzyme A (acetyl-CoA) synthetase enzymes that use acetate to produce acetyl-CoA. Metazoans, however, use glucose as their main carbon source and have exposure only to low concentrations of extracellular acetate. We have shown that histone acetylation in mammalian cells is dependent on adenosine triphosphate (ATP)-citrate lyase (ACL), the enzyme that converts glucose-derived citrate into acetyl-CoA. We found that ACL is required for increases in histone acetylation in response to growth factor stimulation and during differentiation, and that glucose availability can affect histone acetylation in an ACL-dependent manner. Together, these findings suggest that ACL activity is required to link growth factor-induced increases in nutrient metabolism to the regulation of histone acetylation and gene expression.

A Qualitative Study on Organizational Factors Affecting Occupational Accidents

PubMed Central

ESKANDARI, Davood; JAFARI, Mohammad Javad; MEHRABI, Yadollah; KIAN, Mostafa Pouya; CHARKHAND, Hossein; MIRGHOTBI, Mostafa

2017-01-01

Background: Technical, human, operational and organizational factors have been influencing the sequence of occupational accidents. Among them, organizational factors play a major role in causing occupational accidents. The aim of this research was to understand the Iranian safety experts’ experiences and perception of organizational factors. Methods: This qualitative study was conducted in 2015 by using the content analysis technique. Data were collected through semi-structured interviews with 17 safety experts working in Iranian universities and industries and analyzed with a conventional qualitative content analysis method using the MAXQDA software. Results: Eleven organizational factors’ sub-themes were identified: management commitment, management participation, employee involvement, communication, blame culture, education and training, job satisfaction, interpersonal relationship, supervision, continuous improvement, and reward system. The participants considered these factors as effective on occupational accidents. Conclusion: The mentioned 11 organizational factors are probably involved in occupational accidents in Iran. Naturally, improving organizational factors can increase the safety performance and reduce occupational accidents. PMID:28435824

Inferring nucleosome positions with their histone mark annotation from ChIP data

PubMed Central

Mammana, Alessandro; Vingron, Martin; Chung, Ho-Ryun

2013-01-01

Motivation: The nucleosome is the basic repeating unit of chromatin. It contains two copies each of the four core histones H2A, H2B, H3 and H4 and about 147 bp of DNA. The residues of the histone proteins are subject to numerous post-translational modifications, such as methylation or acetylation. Chromatin immunoprecipitiation followed by sequencing (ChIP-seq) is a technique that provides genome-wide occupancy data of these modified histone proteins, and it requires appropriate computational methods. Results: We present NucHunter, an algorithm that uses the data from ChIP-seq experiments directed against many histone modifications to infer positioned nucleosomes. NucHunter annotates each of these nucleosomes with the intensities of the histone modifications. We demonstrate that these annotations can be used to infer nucleosomal states with distinct correlations to underlying genomic features and chromatin-related processes, such as transcriptional start sites, enhancers, elongation by RNA polymerase II and chromatin-mediated repression. Thus, NucHunter is a versatile tool that can be used to predict positioned nucleosomes from a panel of histone modification ChIP-seq experiments and infer distinct histone modification patterns associated to different chromatin states. Availability: The software is available at http://epigen.molgen.mpg.de/nuchunter/. Contact: chung@molgen.mpg.de Supplementary information: Supplementary data are available at Bioinformatics online. PMID:23981350

Occupational Factors, Fatigue, and Cardiovascular Disease

PubMed Central

2009-01-01

Purpose: Briefly identify the epidemiological evidence, propose pertinent mechanisms, and discuss physical therapy practice as well as research implications of a causal association between occupational factors and cardiovascular disease. Summary of Key Points: There is evidence that occupational metabolic demands and work organizations characterized by reduced worker control are associated with increased risk of cardiovascular disease. It is biologically plausible that these two factors interact to create a preclinical, intermediate state of fatigue (burnout) that is a critical component in the causal path from occupational factors to CVD. Physical therapists are uniquely qualified to contribute to an understanding of these mechanisms and their resultant implications for work organization, rehabilitation, and health promotion. Statement of Recommendations: Physical therapists engaged in ergonomic job analysis should consider work related metabolic demands, worker control, and fatigue in their assessment of risk for injury and illness, in recommendations for return to work, and in the prescription of health promotion leisure time physical activity PMID:20467535

Histone ubiquitination: a tagging tail unfolds?

PubMed

Jason, Laure J M; Moore, Susan C; Lewis, John D; Lindsey, George; Ausió, Juan

2002-02-01

Despite the fact that histone H2A ubiquitination affects about 10-15% of this histone in most eukaryotic cells, histone ubiquitination is among one of the less-well-characterized post-translational histone modifications. Nevertheless, some important observations have been made in recent years. Whilst several enzymes had been known to ubiquitinate histones in vitro, recent studies in yeast have led to the unequivocal identification of the enzyme responsible for this post-translational modification in this organism. A strong functional co-relation to meiosis and spermiogenesis has also now been well documented, although its participation in other functional aspects of chromatin metabolism, such as transcription or DNA repair, still remains rather speculative and controversial. Because of its nature, histone ubiquitination represents the most bulky structural change to histones and as such it would be expected to exert an important effect on chromatin structure. Past and recent structural studies, however, indicate a surprising lack of effect of (H2A/H2B) ubiquitination on nucleosome architecture and of uH2A on chromatin folding. These results suggest that this modification may serve as a signal for recognition by functionally relevant trans-acting factors and/or operate synergistically in conjunction with other post-translational modifications such as for instance acetylation. Copyright 2002 Wiley Periodicals, Inc.

Occupational and genetic risk factors for osteoarthritis: A review

PubMed Central

Yucesoy, Berran; Charles, Luenda E.; Baker, Brent; Burchfiel, Cecil M.

2015-01-01

BACKGROUND Osteoarthritis (OA) is a multifactorial disease with strong genetic and occupational components. Although published studies have described several risk factors for OA, very few studies have investigated the occupational and genetic factors that contribute to this debilitating condition. OBJECTIVE To describe occupational and genetic factors that may contribute to the risk of developing (OA). METHODS A literature search was conducted in PubMed using the search terms osteoarthritis, occupation, work, and genetics. RESULTS Heavy physical work load was the most common occupational risk factor for OA in several anatomical locations. Other factors include kneeling and regular stair climbing, crawling, bending and whole body vibration, and repetitive movements. Numerous studies have also shown the influence of genetic variability in the pathogenesis of OA. Genetic variants of several groups of genes e.g., cartilage extracellular matrix structural genes and the genes related to bone density have been implicated in disease pathogenesis. CONCLUSION This review shows that occupational factors were extensively studied in knee OA unlike OA of other anatomical regions. Although genetic association studies performed to date identified a number of risk variants, some of these associations have not been consistently replicated across different studies and populations. Therefore, more research is needed. PMID:24004806

Aggregate Exposure and Cumulative Risk Assessment—Integrating Occupational and Non-occupational Risk Factors

PubMed Central

Lentz, T. J.; Dotson, G. S.; Williams, P. R.D.; Maier, A.; Gadagbui, B.; Pandalai, S. P.; Lamba, A.; Hearl, F.; Mumtaz, M.

2015-01-01

Occupational exposure limits have traditionally focused on preventing morbidity and mortality arising from inhalation exposures to individual chemical stressors in the workplace. While central to occupational risk assessment, occupational exposure limits have limited application as a refined disease prevention tool because they do not account for all of the complexities of the work and non-occupational environments and are based on varying health endpoints. To be of greater utility, occupational exposure limits and other risk management tools could integrate broader consideration of risks from multiple exposure pathways and routes (aggregate risk) as well as the combined risk from exposure to both chemical and non-chemical stressors, within and beyond the workplace, including the possibility that such exposures may cause interactions or modify the toxic effects observed (cumulative risk). Although still at a rudimentary stage in many cases, a variety of methods and tools have been developed or are being used in allied risk assessment fields to incorporate such considerations in the risk assessment process. These approaches, which are collectively referred to as cumulative risk assessment, have potential to be adapted or modified for occupational scenarios and provide a tangible path forward for occupational risk assessment. Accounting for complex exposures in the workplace and the broader risks faced by the individual also requires a more complete consideration of the composite effects of occupational and non-occupational risk factors to fully assess and manage worker health problems. Barriers to integrating these different factors remain, but new and ongoing community-based and worker health-related initiatives may provide mechanisms for identifying and integrating risk from aggregate exposures and cumulative risks from all relevant sources, be they occupational or non-occupational. PMID:26583907

Aggregate Exposure and Cumulative Risk Assessment--Integrating Occupational and Non-occupational Risk Factors.

PubMed

Lentz, T J; Dotson, G S; Williams, P R D; Maier, A; Gadagbui, B; Pandalai, S P; Lamba, A; Hearl, F; Mumtaz, M

2015-01-01

Occupational exposure limits have traditionally focused on preventing morbidity and mortality arising from inhalation exposures to individual chemical stressors in the workplace. While central to occupational risk assessment, occupational exposure limits have limited application as a refined disease prevention tool because they do not account for all of the complexities of the work and non-occupational environments and are based on varying health endpoints. To be of greater utility, occupational exposure limits and other risk management tools could integrate broader consideration of risks from multiple exposure pathways and routes (aggregate risk) as well as the combined risk from exposure to both chemical and non-chemical stressors, within and beyond the workplace, including the possibility that such exposures may cause interactions or modify the toxic effects observed (cumulative risk). Although still at a rudimentary stage in many cases, a variety of methods and tools have been developed or are being used in allied risk assessment fields to incorporate such considerations in the risk assessment process. These approaches, which are collectively referred to as cumulative risk assessment, have potential to be adapted or modified for occupational scenarios and provide a tangible path forward for occupational risk assessment. Accounting for complex exposures in the workplace and the broader risks faced by the individual also requires a more complete consideration of the composite effects of occupational and non-occupational risk factors to fully assess and manage worker health problems. Barriers to integrating these different factors remain, but new and ongoing community-based and worker health-related initiatives may provide mechanisms for identifying and integrating risk from aggregate exposures and cumulative risks from all relevant sources, be they occupational or non-occupational.

Individual and occupational factors related to fatal occupational injuries: a case-control study.

PubMed

Villanueva, Vicent; Garcia, Ana M

2011-01-01

This study has been designed in order to identify factors increasing the risk of a fatal outcome when occupational accidents occur. The aim is to provide further evidence for the design and implementation of preventive measures in occupational settings. The Spanish Ministry of Labour registry of occupational injuries causing absence from work includes information on individual and occupational characteristics of injured workers and events. Registered fatal occupational injuries in 2001 (n=539) were compared to a sample of non-fatal injuries in the same year (n=3493). Risks for a fatal result of occupational injuries, adjusted by individual and occupational factors significantly associated, were obtained through logistic regression models. Compared to non-fatal injuries, fatal occupational injuries were mostly produced by trapping or by natural causes, mostly related to elevation and transport devices and power generators, and injured parts of body more frequently affected were head, multiple parts or internal organs. Adjusted analyses showed increased risk of fatality after an occupational injury for males (adjusted odds ratio aOR=10.92; 95%CI 4.80-24.84) and temporary workers (aOR=5.18; 95%CI 2.63-10.18), and the risk increased with age and with advancing hour of the work shift (p for trends <0.01). Injuries taking place out of the usual occupational setting (aOR=2.85, 95%CI 2.27-3.59), or carrying out atypical tasks (aOR=2.08; 95%CI 1.27-3.39) showed increased risks of a fatal result too, as occupational accidents in agricultural or construction companies. These data can help to select and define priorities for programmes aimed to prevent fatal consequences of occupational injuries. Copyright © 2010 Elsevier Ltd. All rights reserved.

Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation.

PubMed

Zhang, Chun Li; McKinsey, Timothy A; Olson, Eric N

2002-10-01

Class II histone deacetylases (HDACs) 4, 5, 7, and 9 repress muscle differentiation through associations with the myocyte enhancer factor 2 (MEF2) transcription factor. MEF2-interacting transcription repressor (MITR) is an amino-terminal splice variant of HDAC9 that also potently inhibits MEF2 transcriptional activity despite lacking a catalytic domain. Here we report that MITR, HDAC4, and HDAC5 associate with heterochromatin protein 1 (HP1), an adaptor protein that recognizes methylated lysines within histone tails and mediates transcriptional repression by recruiting histone methyltransferase. Promyogenic signals provided by calcium/calmodulin-dependent kinase (CaMK) disrupt the interaction of MITR and HDACs with HP1. Since the histone methyl-lysine residues recognized by HP1 also serve as substrates for deacetylation by HDACs, the interaction of MITR and HDACs with HP1 provides an efficient mechanism for silencing MEF2 target genes by coupling histone deacetylation and methylation. Indeed, nucleosomal histones surrounding a MEF2-binding site in the myogenin gene promoter are highly methylated in undifferentiated myoblasts, when the gene is silent, and become acetylated during muscle differentiation, when the myogenin gene is expressed at high levels. The ability of MEF2 to recruit a histone methyltransferase to target gene promoters via HP1-MITR and HP1-HDAC interactions and of CaMK signaling to disrupt these interactions provides an efficient mechanism for signal-dependent regulation of the epigenetic events controlling muscle differentiation.

Association of Class II Histone Deacetylases with Heterochromatin Protein 1: Potential Role for Histone Methylation in Control of Muscle Differentiation

PubMed Central

Zhang, Chun Li; McKinsey, Timothy A.; Olson, Eric N.

2002-01-01

Class II histone deacetylases (HDACs) 4, 5, 7, and 9 repress muscle differentiation through associations with the myocyte enhancer factor 2 (MEF2) transcription factor. MEF2-interacting transcription repressor (MITR) is an amino-terminal splice variant of HDAC9 that also potently inhibits MEF2 transcriptional activity despite lacking a catalytic domain. Here we report that MITR, HDAC4, and HDAC5 associate with heterochromatin protein 1 (HP1), an adaptor protein that recognizes methylated lysines within histone tails and mediates transcriptional repression by recruiting histone methyltransferase. Promyogenic signals provided by calcium/calmodulin-dependent kinase (CaMK) disrupt the interaction of MITR and HDACs with HP1. Since the histone methyl-lysine residues recognized by HP1 also serve as substrates for deacetylation by HDACs, the interaction of MITR and HDACs with HP1 provides an efficient mechanism for silencing MEF2 target genes by coupling histone deacetylation and methylation. Indeed, nucleosomal histones surrounding a MEF2-binding site in the myogenin gene promoter are highly methylated in undifferentiated myoblasts, when the gene is silent, and become acetylated during muscle differentiation, when the myogenin gene is expressed at high levels. The ability of MEF2 to recruit a histone methyltransferase to target gene promoters via HP1-MITR and HP1-HDAC interactions and of CaMK signaling to disrupt these interactions provides an efficient mechanism for signal-dependent regulation of the epigenetic events controlling muscle differentiation. PMID:12242305

Factors influencing nurses' perceptions of occupational safety.

PubMed

Samur, Menevse; Intepeler, Seyda Seren

2017-01-02

To determine nurses' perceptions of occupational safety and their work environment and examine the sociodemographic traits and job characteristics that influence their occupational safety, we studied a sample of 278 nurses. According to the nurses, the quality of their work environment is average, and occupational safety is insufficient. In the subdimensions of the work environment scale, it was determined that the nurses think "labor force and other resources" are insufficient. In the occupational safety subdimensions "occupational illnesses and complaints" and "administrative support and approaches," they considered occupational safety to be insufficient. "Doctor-nurse-colleague relationships," "exposure to violence," and "work unit" (eg, internal medicine, surgical, intensive care) are the main factors that affect occupational safety. This study determined that hospital administrations should develop and immediately implement plans to ameliorate communication and clinical precautions and to reduce exposure to violence.

Histone acetylation regulates the time of replication origin firing.

PubMed

Vogelauer, Maria; Rubbi, Liudmilla; Lucas, Isabelle; Brewer, Bonita J; Grunstein, Michael

2002-11-01

The temporal firing of replication origins throughout S phase in yeast depends on unknown determinants within the adjacent chromosomal environment. We demonstrate here that the state of histone acetylation of surrounding chromatin is an important regulator of temporal firing. Deletion of RPD3 histone deacetylase causes earlier origin firing and concurrent binding of the replication factor Cdc45p to origins. In addition, increased acetylation of histones in the vicinity of the late origin ARS1412 by recruitment of the histone acetyltransferase Gcn5p causes ARS1412 alone to fire earlier. These data indicate that histone acetylation is a direct determinant of the timing of origin firing.

Endometriosis Is Characterized by a Distinct Pattern of Histone 3 and Histone 4 Lysine Modifications

PubMed Central

Monteiro, Janice B.; Colón-Díaz, Maricarmen; García, Miosotis; Gutierrez, Sylvia; Colón, Mariano; Seto, Edward; Laboy, Joaquín

2014-01-01

Background: The histone modification patterns in endometriosis have not been fully characterized. This gap in knowledge results in a poor understanding of the epigenetic mechanisms (and potential therapeutic targets) at play. We aimed to (1) assess global acetylation status of histone 3 (H3) and histone 4 (H4), (2) measure levels of H3 and H4 lysine (K) acetylation and methylation, and (3) to identify histone acetylation patterns in promoter regions of candidate genes in tissues from patients and controls. Methods: Global and K-specific acetylation/methylation levels of histones were measured in 24 lesions, 15 endometrium from patients, and 26 endometrium from controls. Chromatin immunoprecipitation (ChIP)–polymerase chain reaction was used to determine the histone acetylation status of the promoter regions of candidate genes in tissues. Results: The lesions were globally hypoacetylated at H3 (but not H4) compared to eutopic endometrium from controls. Lesions had significantly lower levels of H3K9ac and H4K16ac compared to eutopic endometrium from patients and controls. Tissues from patients were hypermethylated at H3K4, H3K9, and H3K27 compared to endometrium from controls. The ChIP analysis showed hypoacetylation of H3/H4 within promoter regions of candidate genes known to be downregulated in endometriosis (e.g., HOXA10, ESR1, CDH1, and p21WAF1/Cip1) in lesions versus control endometrium. The stereoidogenic factor 1 (SF1) promoter region was enriched for acetylated H3 and H4 in lesions versus control tissues, correlating with its reported high expression in lesions. Conclusions: This study describes the histone code of lesions and endometrium from patients with endometriosis and provides support for a possible role of histone modification in modulation of gene expression in endometriosis. PMID:23899551

Histone-Targeted Nucleic Acid Delivery for Tissue Regenerative Applications

NASA Astrophysics Data System (ADS)

Munsell, Erik V.

Nucleic acid delivery has garnered significant attention as an innovative therapeutic approach for treating a wide variety of diseases. However, the design of non-viral delivery systems that negotiate efficient intracellular trafficking and nuclear entry represents a significant challenge. Overcoming these hurdles requires a combination of well-controlled materials approaches with techniques to understand and direct cellular delivery. Recent investigations have highlighted the roles histone tail sequences play in directing nuclear delivery and retention, as well as activating DNA transcription. We established the ability to recapitulate these natural histone tail activities within non-viral gene nanocarriers, driving gene transfer/expression by enabling effective navigation to the nucleus via retrograde vesicular trafficking. A unique finding of this histone-targeted approach was that nanocarriers gained enhanced access to the nucleus during mitosis. The work described in this dissertation builds off of these fundamental insights to facilitate the translation of this histone-targeted delivery approach toward regenerative medicine applications. During native tissue repair, actively proliferating mesenchymal stem cells (MSCs) respond to a complex series of growth factor signals that direct their differentiation. Accordingly, the investigations in this work focused on utilizing the histone-targeted nanocarriers to enhance osteogenic growth factor gene transfer in dividing MSCs leading to augmented MSC chondrogenic differentiation, an essential first step in skeletal tissue repair. Concurrently, additional studies focused on optimizing the histone-targeted nanocarrier design strategy to enable improved plasmid DNA (pDNA) binding stability and tunable harnessing of native cellular processing pathways for enhanced gene transfer. Overall, the work presented herein demonstrated substantial increases in growth factor expression following histone-targeted gene transfer. This

Histone methylations in heart development, congenital and adult heart diseases.

PubMed

Zhang, Qing-Jun; Liu, Zhi-Ping

2015-01-01

Heart development comprises myocyte specification, differentiation and cardiac morphogenesis. These processes are regulated by a group of core cardiac transcription factors in a coordinated temporal and spatial manner. Histone methylation is an emerging epigenetic mechanism for regulating gene transcription. Interplay among cardiac transcription factors and histone lysine modifiers plays important role in heart development. Aberrant expression and mutation of the histone lysine modifiers during development and in adult life can cause either embryonic lethality or congenital heart diseases, and influences the response of adult hearts to pathological stresses. In this review, we describe current body of literature on the role of several common histone methylations and their modifying enzymes in heart development, congenital and adult heart diseases.

Factors affecting ethical behavior in pediatric occupational therapy: A qualitative study

PubMed Central

Kalantari, Minoo; Kamali, Mohammad; Joolaee, Soodabeh; Shafarodi, Narges; Rassafiani, Mehdi

2015-01-01

Background: It is the responsibility of each occupational therapist to always act ethically and professionally in a clinical setting. However, there is little information available concerning the factors influencing ethical behavior of occupational therapists at work. Since no study has been conducted in Iran on this topic, this qualitative study aimed to identify the factors influencing ethical behavior of pediatric occupational therapists. Methods: Twelve pediatric occupational therapists participated in this study. The sampling was purposeful, and the interviews continued until reaching data saturation. All interviews were recorded and transcribed. The data were analyzed by qualitative content analysis, and the ethics of qualitative research was considered. Results: The factors influencing ethical behavior were classified into four main categories including organizational factors, therapist related factors, client’s family issues, and social factors. Conclusion: This study identified numerous factors influencing the ethical behavior of pediatric occupational therapists that could be used to train occupational therapists, human resources managers, professional policy makers, and could also be used to conduct future researches, and produce tools. PMID:26913245

Histone chaperone APLF regulates induction of pluripotency in murine fibroblasts.

PubMed

Syed, Khaja Mohieddin; Joseph, Sunu; Mukherjee, Ananda; Majumder, Aditi; Teixeira, Jose M; Dutta, Debasree; Pillai, Madhavan Radhakrishna

2016-12-15

Induction of pluripotency in differentiated cells through the exogenous expression of the transcription factors Oct4, Sox2, Klf4 and cellular Myc involves reprogramming at the epigenetic level. Histones and their metabolism governed by histone chaperones constitute an important regulator of epigenetic control. We hypothesized that histone chaperones facilitate or inhibit the course of reprogramming. For the first time, we report here that the downregulation of histone chaperone Aprataxin PNK-like factor (APLF) promotes reprogramming by augmenting the expression of E-cadherin (Cdh1), which is implicated in the mesenchymal-to-epithelial transition (MET) involved in the generation of induced pluripotent stem cells (iPSCs) from mouse embryonic fibroblasts (MEFs). Downregulation of APLF in MEFs expedites the loss of the repressive MacroH2A.1 (encoded by H2afy) histone variant from the Cdh1 promoter and enhances the incorporation of active histone H3me2K4 marks at the promoters of the pluripotency genes Nanog and Klf4, thereby accelerating the process of cellular reprogramming and increasing the efficiency of iPSC generation. We demonstrate a new histone chaperone (APLF)-MET-histone modification cohort that functions in the induction of pluripotency in fibroblasts. This regulatory axis might provide new mechanistic insights into perspectives of epigenetic regulation involved in cancer metastasis. © 2016. Published by The Company of Biologists Ltd.

Cell cycle-regulated oscillator coordinates core histone gene transcription through histone acetylation

PubMed Central

Kurat, Christoph F.; Lambert, Jean-Philippe; Petschnigg, Julia; Friesen, Helena; Pawson, Tony; Rosebrock, Adam; Gingras, Anne-Claude; Fillingham, Jeffrey; Andrews, Brenda

2014-01-01

DNA replication occurs during the synthetic (S) phase of the eukaryotic cell cycle and features a dramatic induction of histone gene expression for concomitant chromatin assembly. Ectopic production of core histones outside of S phase is toxic, underscoring the critical importance of regulatory pathways that ensure proper expression of histone genes. Several regulators of histone gene expression in the budding yeast Saccharomyces cerevisiae are known, yet the key oscillator responsible for restricting gene expression to S phase has remained elusive. Here, we show that suppressor of Ty (Spt)10, a putative histone acetyltransferase, and its binding partner Spt21 are key determinants of S-phase–specific histone gene expression. We show that Spt21 abundance is restricted to S phase in part by anaphase promoting complex Cdc20-homologue 1 (APCCdh1) and that it is recruited to histone gene promoters in S phase by Spt10. There, Spt21-Spt10 enables the recruitment of a cascade of regulators, including histone chaperones and the histone-acetyltransferase general control nonderepressible (Gcn) 5, which we hypothesize lead to histone acetylation and consequent transcription activation. PMID:25228766

Chronic cough due to occupational factors

PubMed Central

Groneberg, David A; Nowak, Dennis; Wussow, Anke; Fischer, Axel

2006-01-01

Within the large variety of subtypes of chronic cough, either defined by their clinical or pathogenetic causes, occupational chronic cough may be regarded as one of the most preventable forms of the disease. Next to obstructive airway diseases such as asthma or chronic obstructive pulmonary disease, which are sometimes concomitant with chronic cough, this chronic airway disease gains importance in the field of occupational medicine since classic fiber-related occupational airway diseases will decrease in the future. Apart from acute accidents and incidental exposures which may lead to an acute form of cough, there are numerous sources for the development of chronic cough within the workplace. Over the last years, a large number of studies has focused on occupational causes of respiratory diseases and it has emerged that chronic cough is one of the most prevalent work-related airway diseases. Best-known examples of occupations related to the development of cough are coal miners, hard-rock miners, tunnel workers, or concrete manufacturing workers. As chronic cough is often based on a variety of non-occupational factors such as tobacco smoke, a distinct separation into either occupational or personally -evoked can be difficult. However, revealing the occupational contribution to chronic cough and to the symptom cough in general, which is the commonest cause for the consultation of a physician, can significantly lead to a reduction of the socioeconomic burden of the disease. PMID:16722562

Occupational stress and related factors among surgical residents in Korea.

PubMed

Kang, Sanghee; Jo, Hye Sung; Boo, Yoon Jung; Lee, Ji Sung; Kim, Chong Suk

2015-11-01

The application rate for surgical residents in Korea has continuously decreased over the past few years. The demanding workload and the occupational stress of surgical training are likely causes of this problem. The aim of this study was to investigate occupational stress and its related factors in Korean surgical residents. With the support of the Korean Surgical Society, we conducted an electronic survey of Korean surgical residents related to occupational stress. We used the Korean Occupational Stress Scale (KOSS) to measure occupational stress. We analyzed the data focused on the stress level and the factors associated with occupational stress. The mean KOSS score of the surgical residents was 55.39, which was significantly higher than that of practicing surgeons (48.16, P < 0.001) and the average score of specialized professionals (46.03, P < 0.001). Exercise was the only factor found to be significantly associated with KOSS score (P = 0.001) in univariate analysis. However, in multiple linear regression analysis, the mean number of assigned patients, resident occupation rate and exercise were all significantly associated with KOSS score. Surgical residents have high occupational stress compared to practicing surgeons and other professionals. Their mean number of assigned patients, resident recruitment rate and exercise were all significantly associated with occupational stress for surgical residents.

Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

PubMed Central

Seto, Edward; Yoshida, Minoru

2014-01-01

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. In humans, there are 18 HDAC enzymes that use either zinc- or NAD+-dependent mechanisms to deacetylate acetyl lysine substrates. Although removal of histone acetyl epigenetic modification by HDACs regulates chromatin structure and transcription, deacetylation of nonhistones controls diverse cellular processes. HDAC inhibitors are already known potential anticancer agents and show promise for the treatment of many diseases. PMID:24691964

Occupational stress and related factors among surgical residents in Korea

PubMed Central

Kang, Sanghee; Jo, Hye Sung; Lee, Ji Sung; Kim, Chong Suk

2015-01-01

Purpose The application rate for surgical residents in Korea has continuously decreased over the past few years. The demanding workload and the occupational stress of surgical training are likely causes of this problem. The aim of this study was to investigate occupational stress and its related factors in Korean surgical residents. Methods With the support of the Korean Surgical Society, we conducted an electronic survey of Korean surgical residents related to occupational stress. We used the Korean Occupational Stress Scale (KOSS) to measure occupational stress. We analyzed the data focused on the stress level and the factors associated with occupational stress. Results The mean KOSS score of the surgical residents was 55.39, which was significantly higher than that of practicing surgeons (48.16, P < 0.001) and the average score of specialized professionals (46.03, P < 0.001). Exercise was the only factor found to be significantly associated with KOSS score (P = 0.001) in univariate analysis. However, in multiple linear regression analysis, the mean number of assigned patients, resident occupation rate and exercise were all significantly associated with KOSS score. Conclusion Surgical residents have high occupational stress compared to practicing surgeons and other professionals. Their mean number of assigned patients, resident recruitment rate and exercise were all significantly associated with occupational stress for surgical residents. PMID:26576407

Occupational risk factors for female breast cancer: a review.

PubMed Central

Goldberg, M S; Labrèche, F

1996-01-01

OBJECTIVES: Although progress has been made in identifying personal risk factors and in improving treatment for female breast cancer, incidence rates continue to increase. With women now occupying a sizable fraction of the workforce, it is worth inquiring whether there are occupational risk factors for breast cancer. This is a review of occupational studies on female breast cancer. METHODS: Suitable reports and published articles with associations of female breast cancer and occupation were identified from technical reports, by searching the MEDLINE bibliographic data base, and by reviewing each paper on cancer that was published in 20 major journals during the period from about 1971-94. RESULTS: A total of 115 studies were identified; 19 studies relied exclusively on data collected for administrative purposes, and there were four incident case-control studies and 92 cohort studies. Although data for individual industries, occupations, and exposures were sparse, there was limited evidence of an association with employment in the pharmaceutical industry and among cosmetologists and beauticians. Associations were also found for chemists and occupations with possible exposure to extremely low frequency electromagnetic fields, but potential methodological weaknesses preclude drawing any definite conclusions. There was little support for increased risks among textiles workers, dry cleaning workers, and nuclear industry workers. CONCLUSIONS: Few high quality occupational studies directed specifically toward women have been carried out to allow the unambiguous identification of occupational risk factors for breast cancer. It is suggested that investigations that account for non-occupational risk factors and that assess exposure in a more detailed way be carried out. One strategy already suggested is to conduct population based, case-control studies in which subjects are interviewed about their occupational histories and exposure to chemical and physical agents which are

Constitutional and occupational risk factors associated with bladder cancer

PubMed Central

Ferrís, J.; Garcia, J.; Berbel, O.; Ortega, J.A.

2016-01-01

Objective Bladder carcinoma (BC) is the fourth most common type of cancer in males from Western countries, with primary prevention an important healthcare challenge. We review the associated constitutional and occupational risk factors (RF), with greater or lesser scientific evidence, in the etiology of BC. Material and methods Literature review of the last 25 years of the constitutional and occupational RF associated with BC, conducted on MedLine, CancerLit, Science Citation Index and Embase. The search profiles were Risk factors/Genetic factors/Genetic polymorphisms/Epidemiology/Occupational factors and Bladder cancer. Results The main RF were (a) age and gender (diagnosed at age 65 and over, with a 4:1 ratio of males to females); (b) race, ethnicity and geographic location (predominantly in Caucasians and in Southern European countries); (c) genetic (N-acetyltransferase-2 and glutathione s-transferase M1 gene mutations, which significantly increase the risk for BC); (d) occupational, which represent 5–10% of BC RF; and (f) occupations with high BC risk, such as aluminum production, the manufacture of dyes, paints and colourings, the rubber industry and the extraction and industrial use of fossil fuels. Conclusions BC is the end result of the variable combination of constitutional and environmental RF, the majority of which are unknown. The most significant constitutional RF are related to age, gender, race, ethnicity geographic location and genetic polymorphisms. The main occupational RF are those related to aromatic amines and polycyclic aromatic hydrocarbons. PMID:23664103

Constitutional and occupational risk factors associated with bladder cancer.

PubMed

Ferrís, J; Garcia, J; Berbel, O; Ortega, J A

2013-09-01

Bladder carcinoma (BC) is the fourth most common type of cancer in males from Western countries, with primary prevention an important healthcare challenge. We review the associated constitutional and occupational risk factors (RF), with greater or lesser scientific evidence, in the aetiology of BC. Literature review of the last 25 years of the constitutional and occupational RF associated with BC, conducted on MedLine, CancerLit, Science Citation Index and Embase. The search profiles were Risk factors/Genetic factors/Genetic polymorphisms/Epidemiology/Occupational factors and Bladder cancer. The main RF were a) age and gender (diagnosed at age 65 and over, with a 4:1 ratio of males to females); b) race, ethnicity and geographic location (predominantly in Caucasians and in Southern European countries); c) genetic (N-acetyltransferase-2 and glutathione s-transferase M1 gene mutations, which significantly increase the risk for BC); d) occupational, which represent 5%-10% of BC RF; and f) occupations with high BC risk, such as aluminium production, the manufacture of dyes, paints and colourings, the rubber industry and the extraction and industrial use of fossil fuels. BC is the end result of the variable combination of constitutional and environmental RF, the majority of which are unknown. The most significant constitutional RF are related to age, gender, race, ethnicity geographic location and genetic polymorphisms. The main occupational RF are those related to aromatic amines and polycyclic aromatic hydrocarbons. Copyright © 2013 AEU. Published by Elsevier Espana. All rights reserved.

Resveratrol Reactivates Latent HIV through Increasing Histone Acetylation and Activating Heat Shock Factor 1.

PubMed

Zeng, Xiaoyun; Pan, Xiaoyan; Xu, Xinfeng; Lin, Jian; Que, Fuchang; Tian, Yuanxin; Li, Lin; Liu, Shuwen

2017-06-07

The persistence of latent HIV reservoirs presents a significant challenge to viral eradication. Effective latency reversing agents (LRAs) based on "shock and kill" strategy are urgently needed. The natural phytoalexin resveratrol has been demonstrated to enhance HIV gene expression, although its mechanism remains unclear. In this study, we demonstrated that resveratrol was able to reactivate latent HIV without global T cell activation in vitro. Mode of action studies showed resveratrol-mediated reactivation from latency did not involve the activation of silent mating type information regulation 2 homologue 1 (SIRT1), which belonged to class-3 histone deacetylase (HDAC). However, latent HIV was reactivated by resveratrol mediated through increasing histone acetylation and activation of heat shock factor 1 (HSF1). Additionally, synergistic activation of the latent HIV reservoirs was observed under cotreatment with resveratrol and conventional LRAs. Collectively, this research reveals that resveratrol is a natural LRA and shows promise for HIV therapy.

Organisational factors and occupational balance in working parents in Sweden.

PubMed

Borgh, Madeleine; Eek, Frida; Wagman, Petra; Håkansson, Carita

2018-05-01

Parents with small children constitute a vulnerable group as they have an increased risk of sick leave due to stress-related disorders compared to adults without children. It has been shown that mothers and fathers to small children together spend more time in paid work than any other group, which could create negative stress and an experience of low occupational balance. The aim of this study was to examine associations between organisational factors and occupational balance among parents with small children in Sweden. Data were collected by a survey including questions about occupational balance, organisational factors and age, sex, employment rate, work position, monthly household income, number of children at home, separation/divorce last five years and overtime. The total number of parents included in this study was 718 (490 mothers and 228 fathers). Logistic regression models were applied to examine the odds ratios for occupational balance in relation to organisational factors. Parents who experienced positive attitudes towards parenthood and parental leave among colleagues and managers were more likely to experience high occupational balance than parents who experienced negative or neutral attitudes. Having a clear structure for handover when absent from work was also strongly associated with high occupational balance. The result of the present study indicates that some organisational factors could be important for the occupational balance of parents with small children.

Occupational Risk Factors of Lymphohematopoietic Cancer in Rayong Province, Thailand.

PubMed

Punjindasup, Apinya; Sangrajrang, Suleeporn; Ekpanyaskul, Chatchai

2015-11-01

The Lymphohematopoietic Cancer (LHC) incidence rate in Thailand has been rising over the past decade with unknown etiology, including Rayong province. One hypothesis of LHC risks is exposure to occupational carcinogens. To determine the association of occupational exposure and LHC risks in Rayong province, Thailand. This matched hospital-based case-control study was conducted in a Rayong provincial hospital from September 2009 to January 2013. One LHC case was matched with four controls in gender and age, ±5 years. Demographic data, residential factors, behavioral factors, and occupational exposure-including chemical exposure-were obtained by interviews and collected by occupational health care officers. The risk factor was analyzed by conditional logistic regression and reported in odds ratio with 95% confidence interval. This study found 105 LHC cases which met the inclusion criteria and were included in the study, yielding a 66% cover rate of cases reported in the database. The histology of LHC were 51 leukemia cases (47.7%), 43 lymphoma cases (42.0%), and 11 multiple myeloma cases (10.3%). The results revealed that occupational exposure to pesticide and smoke were statistically significantly associated with LHC with adjusted ORs 2.26 (95% CI 1.30-3.91) and 1.99 (95% CI = 1.13-3.51), respectively. When stratified to histological subtype of LHC by WHO 2000, leukemia was statistically significantly associated with occupational exposure to smoke, adjusted ORs 2.43 (95% CI 1.11-5.36), with occupational pesticide exposure a significant risk of lymphoma, adjusted ORs 4.69 (95% CI 2.01-10.96). However, neither fumes, wood dust, working outdoors, cleaners, contact with animals, petroleum products and chlorine; nor occupational exposure to volatile organic compounds (VOCs) such as benzene or organic solvents, were statistically significant risk factors of LHC. In addition, there were no significant risks in the demographic data, residential factors, and behavioral

The chaperone-histone partnership: for the greater good of histone traffic and chromatin plasticity.

PubMed

Hondele, Maria; Ladurner, Andreas G

2011-12-01

Histones are highly positively charged proteins that wrap our genome. Their surface properties also make them prone to nonspecific interactions and aggregation. A class of proteins known as histone chaperones is dedicated to safeguard histones by aiding their proper incorporation into nucleosomes. Histone chaperones facilitate ordered nucleosome assembly and disassembly reactions through the formation of semi-stable histone-chaperone intermediates without requiring ATP, but merely providing a complementary protein surface for histones to dynamically interact with. Recurrent 'chaperoning' mechanisms involve the masking of the histone's positive charge and the direct blocking of crucial histone surface sites, including those required for H3-H4 tetramerization or the binding of nucleosomal DNA. This shielding prevents histones from engaging in premature or unwanted interactions with nucleic acids and other cellular components. In this review, we analyze recent structural studies on chaperone-histone interactions and discuss the implications of this vital partnership for nucleosome assembly and disassembly pathways. Copyright © 2011 Elsevier Ltd. All rights reserved.

Histone arginine methylations: their roles in chromatin dynamics and transcriptional regulation

PubMed Central

LITT, Michael; QIU, Yi; HUANG, Suming

2017-01-01

Synopsis PRMTs (protein arginine N-methyltransferases) specifically modify the arginine residues of key cellular and nuclear proteins as well as histone substrates. Like lysine methylation, transcriptional repression or activation is dependent upon the site and type of arginine methylation on histone tails. Recent discoveries imply that histone arginine methylation is an important modulator of dynamic chromatin regulation and transcriptional controls. However, under the shadow of lysine methylation, the roles of histone arginine methylation have been under-explored. The present review focuses on the roles of histone arginine methylation in the regulation of gene expression, and the interplays between histone arginine methylation, histone acetylation, lysine methylation and chromatin remodelling factors. In addition, we discuss the dynamic regulation of arginine methylation by arginine demethylases, and how dysregulation of PRMTs and their activities are linked to human diseases such as cancer. PMID:19220199

Occupational factors and pancreatic cancer.

PubMed Central

Norell, S; Ahlbom, A; Olin, R; Erwald, R; Jacobson, G; Lindberg-Navier, I; Wiechel, K L

1986-01-01

The relation between occupational factors and pancreatic cancer has been studied by two different approaches: a population based case-control study with two series of controls and a retrospective cohort study based on register data. With both approaches, some support was found for an association with occupational exposure to petroleum products. Associations were also indicated with exposure to paint thinner (case-control study) and work in painting and in paint and varnish factories (cohort study), for exposure to detergents, floor cleaning agents, or polish (case-control study) and with floor polishing or window cleaning (cohort study), and for exposure to refuse (case-control study) and work in refuse disposal plants (cohort study). PMID:3790458

SIRT3 restricts HBV transcription and replication via epigenetic regulation of cccDNA involving SUV39H1 and SETD1A histone methyltransferases.

PubMed

Ren, Ji-Hua; Hu, Jie-Li; Cheng, Sheng-Tao; Yu, Hai-Bo; Wong, Vincent Kam Wai; Law, Betty Yuen Kwan; Yang, Yong-Feng; Huang, Ying; Liu, Yi; Chen, Wei-Xian; Cai, Xue-Fei; Tang, Hua; Hu, Yuan; Zhang, Wen-Lu; Liu, Xiang; Long, Quan-Xin; Zhou, Li; Tao, Na-Na; Zhou, Hong-Zhong; Yang, Qiu-Xia; Ren, Fang; He, Lin; Gong, Rui; Huang, Ai-Long; Chen, Juan

2018-04-06

Hepatitis B virus (HBV) infection remains a major health problem worldwide. Maintenance of the covalently closed circular DNA (cccDNA) which serves as a template for HBV RNA transcription is responsible for the failure of eradicating chronic HBV during current antiviral therapy. cccDNA is assembled with cellular histone proteins into chromatin, but little is known about the regulation of HBV chromatin by histone posttranslational modifications. In this study, we identified SIRT3 as a host factor restricting HBV transcription and replication by screening seven members of Sirtuin family which is the class III histone deacetylase. Ectopic SIRT3 expression significantly reduced total HBV RNAs, 3.5-kb RNA as well as replicative intermediate DNA in HBV-infected HepG2-NTCP cells and PHH. In contrast, gene silencing of SIRT3 promoted HBV transcription and replication. Mechanistic study found nuclear SIRT3 was recruited to the HBV cccDNA, where it deacetylated histone 3 lysine 9 (H3K9). Importantly, occupancy of SIRT3 onto cccDNA could increase the recruitment of histone methyltransferase SUV39H1 to cccDNA and decrease recruitment of SETD1A, leading to a marked increase of H3K9me3 and a decrease of H3K4me3 on cccDNA. Moreover, SIRT3-mediated HBV cccDNA transcriptional repression involved decreased binding of host RNA polymerase II and transcription factor YY1 to cccDNA. Finally, viral protein HBx could relieve SIRT3-mediated cccDNA transcriptional repression by inhibiting both SIRT3 expression and its recruitment to cccDNA. SIRT3 is a novel host factor epigenetically restricting HBV cccDNA transcription by acting cooperatively with histone methyltransferase. These data provided a rational for the use of SIRT3 activators in the prevention or treatment of HBV infection. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

HIstome--a relational knowledgebase of human histone proteins and histone modifying enzymes.

PubMed

Khare, Satyajeet P; Habib, Farhat; Sharma, Rahul; Gadewal, Nikhil; Gupta, Sanjay; Galande, Sanjeev

2012-01-01

Histones are abundant nuclear proteins that are essential for the packaging of eukaryotic DNA into chromosomes. Different histone variants, in combination with their modification 'code', control regulation of gene expression in diverse cellular processes. Several enzymes that catalyze the addition and removal of multiple histone modifications have been discovered in the past decade, enabling investigations of their role(s) in normal cellular processes and diverse pathological conditions. This sudden influx of data, however, has resulted in need of an updated knowledgebase that compiles, organizes and presents curated scientific information to the user in an easily accessible format. Here, we present HIstome, a browsable, manually curated, relational database that provides information about human histone proteins, their sites of modifications, variants and modifying enzymes. HIstome is a knowledgebase of 55 human histone proteins, 106 distinct sites of their post-translational modifications (PTMs) and 152 histone-modifying enzymes. Entries have been grouped into 5 types of histones, 8 types of post-translational modifications and 14 types of enzymes that catalyze addition and removal of these modifications. The resource will be useful for epigeneticists, pharmacologists and clinicians. HIstome: The Histone Infobase is available online at http://www.iiserpune.ac.in/∼coee/histome/ and http://www.actrec.gov.in/histome/.

Dynamic intramolecular regulation of the histone chaperone nucleoplasmin controls histone binding and release

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warren, Christopher; Matsui, Tsutomu; Karp, Jerome M.

Here, nucleoplasmin (Npm) is a highly conserved histone chaperone responsible for the maternal storage and zygotic release of histones H2A/H2B. Npm contains a pentameric N-terminal core domain and an intrinsically disordered C-terminal tail domain. Though intrinsically disordered regions are common among histone chaperones, their roles in histone binding and chaperoning remain unclear. Using an NMR-based approach, here we demonstrate that the Xenopus laevis Npm tail domain controls the binding of histones at its largest acidic stretch (A2) via direct competition with both the C-terminal basic stretch and basic nuclear localization signal. NMR and small-angle X-ray scattering (SAXS) structural analyses allowedmore » us to construct models of both the tail domain and the pentameric complex. Functional analyses demonstrate that these competitive intramolecular interactions negatively regulate Npm histone chaperone activity in vitro. Together these data establish a potentially generalizable mechanism of histone chaperone regulation via dynamic and specific intramolecular shielding of histone interaction sites.« less

Dynamic intramolecular regulation of the histone chaperone nucleoplasmin controls histone binding and release

DOE PAGES

Warren, Christopher; Matsui, Tsutomu; Karp, Jerome M.; ...

2017-12-20

Here, nucleoplasmin (Npm) is a highly conserved histone chaperone responsible for the maternal storage and zygotic release of histones H2A/H2B. Npm contains a pentameric N-terminal core domain and an intrinsically disordered C-terminal tail domain. Though intrinsically disordered regions are common among histone chaperones, their roles in histone binding and chaperoning remain unclear. Using an NMR-based approach, here we demonstrate that the Xenopus laevis Npm tail domain controls the binding of histones at its largest acidic stretch (A2) via direct competition with both the C-terminal basic stretch and basic nuclear localization signal. NMR and small-angle X-ray scattering (SAXS) structural analyses allowedmore » us to construct models of both the tail domain and the pentameric complex. Functional analyses demonstrate that these competitive intramolecular interactions negatively regulate Npm histone chaperone activity in vitro. Together these data establish a potentially generalizable mechanism of histone chaperone regulation via dynamic and specific intramolecular shielding of histone interaction sites.« less

Risk factors for occupational acute mountain sickness.

PubMed

Vinnikov, D; Brimkulov, N; Krasotski, V; Redding-Jones, R; Blanc, P D

2014-10-01

Studies of occupational acute mountain sickness (AMS) have not focused on the more severe end of the spectrum to date. To examine risk factors associated with the development of occupational AMS severe enough to receive treatment in a compression chamber. A nested case referent study in a cohort of high-altitude (4000 m) mine workers, comparing cases of severe, chamber-treated AMS to matched referents. Using logistic regression, we tested potential risk factors based on premorbid surveillance examinations, including cigarette smoking (current smoking, smoking intensity and exhaled carbon monoxide [CO]). There were 15 cases and 30 controls. In multivariate analysis including age, sex and place of residence, current smoking was associated with increased risk of severe AMS (odds ratio [OR] 10.0; 95% confidence interval [CI] 1.5-67.4), taking into account any prior, less severe AMS event, which was also a potent risk factor (OR 33.3; 95% CI 2.8-390). Smoking intensity (cigarettes per day) and exhaled CO were also statistically significantly associated with severe AMS. Cigarette smoking is a strong, previously under-appreciated risk factor for severe AMS. Because this is a modifiable factor, these findings suggest that workplace-based smoking cessation should be tested as an intervention to prevent such morbidity. © The Author 2014. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Histone Arginine Methylation

PubMed Central

Lorenzo, Alessandra Di; Bedford, Mark T.

2012-01-01

Arginine methylation is a common posttranslational modification (PTM). This type of PTM occurs on both nuclear and cytoplasmic proteins, and is particularly abundant on shuttling proteins. In this review, we will focus on one aspect of this PTM: the diverse roles that arginine methylation of the core histone tails play in regulating chromatin function. A family of nine protein arginine methyltransferases (PRMTs) catalyze methylation reactions, and a subset target histones. Importantly, arginine methylation of histone tails can promote or prevent the docking of key transcriptional effector molecules, thus playing a central role in the orchestration of the histone code. PMID:21074527

[Appraisal of occupational stress and its influential factors in nurses].

PubMed

Yang, Xin-wei; Wang, Zhi-ming; Wang, Mian-zhen; Lan, Ya-jia

2004-04-01

To assess the occupational stress and its influential factors in nurses. A test of occupational stress, its influential factors, work ability were carried out for 248 nurses and 319 controls with revised occupational stress inventory (OSI-R) and work ability index (WAI). The scores of personal cope resource (131.266 +/- 17.176) and work ability index (32.581 +/- 3.158) in nurse group were significantly higher than those in control group (126.931 +/- 19.108, 31.840 +/- 4.069) (P < 0.05). The main occupational stressors scores (role insufficiency, role clash, and responsibility) in nurses were higher than those in controls (P < 0.05). The stress response of interpersonal relationship in nurses was also higher. The items of personal cope resource, such as recreation, self-care and social support of nurses were superior to those of controls (P < 0.05). Stress response was positively correlated with occupational role (r = 0.512, P < 0.01), and negatively correlated with the personal cope resource (r = -0.475, P < 0.01). The primary influential factors of personal stress were recreation, social support, rational conduct, role insufficiency, role clash, responsibility, and poor work environment. To strengthen social support, to improve work condition for nurses, so as to reduce the occupational stress and to enhance the work ability of nurses are important task in occupational health field.

Tunicate cytostatic factor TC14-3 induces a polycomb group gene and histone modification through Ca2+ binding and protein dimerization

PubMed Central

2012-01-01

Background As many invertebrate species have multipotent cells that undergo cell growth and differentiation during regeneration and budding, many unique and interesting homeostatic factors are expected to exist in those animals. However, our understanding of such factors and global mechanisms remains very poor. Single zooids of the tunicate, Polyandrocarpa misakiensis, can give off as many as 40 buds during the life span. Bud development proceeds by means of transdifferentiation of very limited number of cells and tissues. TC14-3 is one of several different but closely related polypeptides isolated from P. misakiensis. It acts as a cytostatic factor that regulates proliferation, adhesion, and differentiation of multipotent cells, although the molecular mechanism remains uncertain. The Polycomb group (PcG) genes are involved in epigenetic control of genomic activity in mammals. In invertebrates except Drosophila, PcG and histone methylation have not been studied so extensively, and genome-wide gene regulation is poorly understood. Results When Phe65 of TC14-3 was mutated to an acidic amino acid, the resultant mutant protein failed to dimerize. The replacement of Thr69 with Arg69 made dimers unstable. When Glu106 was changed to Gly106, the resultant mutant protein completely lost Ca2+ binding. All these mutant proteins lacked cytostatic activity, indicating the requirement of protein dimerization and calcium for the activity. Polyandrocarpa Eed, a component of PcG, is highly expressed during budding, like TC14-3. When wild-type and mutant TC14-3s were applied in vivo and in vitro to Polyandrocarpa cells, only wild-type TC14-3 could induce Eed without affecting histone methyltransferase gene expression. Eed-expressing cells underwent trimethylation of histone H3 lysine27. PmEed knockdown by RNA interference rescued cultured cells from the growth-inhibitory effects of TC14-3. Conclusion These results show that in P. misakiensis, the cytostatic activity of TC14-3 is

Occupational risk factors in inflammatory bowel disease.

PubMed

Leso, V; Ricciardi, W; Iavicoli, I

2015-08-01

Crohn's disease and ulcerative colitis are the two main forms of inflammatory bowel disease (IBD). Although the aetiology of IBD is not completely understood, an interaction between genetic and environmental factors has been proposed. In this context, however, environmental epidemiology lacks a comprehensive evaluation of the possible role of occupational exposures in IBD development and progression. Therefore, aim of our review was to evaluate how certain occupational risk factors may affect IBD pathogenesis, clinical history and severity of disease manifestations. A critical revision of available literature concerning exposure to groups of potential workplace hazardous agents and IBD, as it appears in Medline and Web of knowledge, was performed. The role of workplace exposures to chemical and biological agents, ionizing or non-ionizing radiations, shift-works, indoor, and sedentary works as well as job strain on IBD has been critically revised. However, the limited number of studies addressing these issues prevented us from extrapolating definite conclusions. Our review pointed out some critical aspects concerning the relationship between occupational factors and IBD, in terms of causative pathways, hazardous exposure, susceptibility and consequences of IBD functional limitations on career choice and fitness for work that need future investigations. Overall, this seems a challenging public health issue, considering the strong IBD impact on patients' quality of life, work productivity and costs to society. Moreover, this review may encourage concerted actions of health care specialists, occupational physicians, employers and IBD workers to plan preventive and protective measures for "healthier patterns of work" for IBD and to develop innovative perspectives for an integrated management of "IBD at work".

Background factors related to and/or influencing occupation in mentally disordered offenders.

PubMed

Lindstedt, Helena; Ivarsson, Ann-Britt; Söderlund, Anne

2006-09-01

Knowledge of background and occupational related factors of mentally disordered offenders are missing. It is essential to understand these issues when planning discharge from forensic psychiatric hospital care to enable community dwelling. One aim was to investigate mentally disordered offenders' background factors, confidence in and how they value occupations. Another aim was to investigate MDOs background factors' in relation to and the influences on Occupational Performance and Social Participation. Data was collected with an explorative, correlative design after informed consent, from 74 mentally disordered offenders (mean age 34,2) cared for in forensic psychiatric hospitals. Assessments were Allen Cognitive Level Screen, Capability to Perform Daily Occupations, Interview Schedule of Social Interaction, Manchester Short Assessment of Quality of Life, Self-efficacy Scale and Importance scale. Eight background factors were assembled from the individual forensic psychiatric investigation. Most of the investigated background factors relate to and half of them influence occupational performance, particular the cognitive aspect of occupational performance. The influences on occupation originate from adulthood, such as suffering from schizophrenia, psycho/social problems, and having performed violent crimes. These findings indicate that staff in forensic hospital care should initiate rehabilitation with knowledge about MDOs' complex daily occupations. For avoiding information bias, information gathering preceding treatment planning should be performed in collaboration between caring staff and mentally disordered offenders.

Eviction of linker histone H1 by NAP-family histone chaperones enhances activated transcription.

PubMed

Zhang, Qian; Giebler, Holli A; Isaacson, Marisa K; Nyborg, Jennifer K

2015-01-01

In the Metazoan nucleus, core histones assemble the genomic DNA to form nucleosome arrays, which are further compacted into dense chromatin structures by the linker histone H1. The extraordinary density of chromatin creates an obstacle for accessing the genetic information. Regulation of chromatin dynamics is therefore critical to cellular homeostasis, and histone chaperones serve as prominent players in these processes. In the current study, we examined the role of specific histone chaperones in negotiating the inherently repressive chromatin structure during transcriptional activation. Using a model promoter, we demonstrate that the human nucleosome assembly protein family members hNap1 and SET/Taf1β stimulate transcription in vitro during pre-initiation complex formation, prior to elongation. This stimulatory effect is dependent upon the presence of activators, p300, and Acetyl-CoA. We show that transcription from our chromatin template is strongly repressed by H1, and that both histone chaperones enhance RNA synthesis by overcoming H1-induced repression. Importantly, both hNap1 and SET/Taf1β directly bind H1, and function to enhance transcription by evicting the linker histone from chromatin reconstituted with H1. In vivo studies demonstrate that SET/Taf1β, but not hNap1, strongly stimulates activated transcription from the chromosomally-integrated model promoter, consistent with the observation that SET/Taf1β is nuclear, whereas hNap1 is primarily cytoplasmic. Together, these observations indicate that SET/Taf1β may serve as a critical regulator of H1 dynamics and gene activation in vivo. These studies uncover a novel function for SET that mechanistically couples transcriptional derepression with H1 dynamics. Furthermore, they underscore the significance of chaperone-dependent H1 displacement as an essential early step in the transition of a promoter from a dense chromatin state into one that is permissive to transcription factor binding and robust

Epigenetic Transgenerational Inheritance of Altered Sperm Histone Retention Sites.

PubMed

Ben Maamar, Millissia; Sadler-Riggleman, Ingrid; Beck, Daniel; Skinner, Michael K

2018-03-28

A variety of environmental toxicants and factors have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. Epigenetic alterations in the germline (sperm or egg) are required to transmit transgenerational phenotypes. The current study was designed to investigate the potential role of histones in sperm to help mediate the epigenetic transgenerational inheritance. The agricultural fungicide vinclozolin and the pesticide DDT (dichlorodiphenyltrichloroethane) were independently used to promote the epigenetic transgenerational inheritance of disease. Purified cauda epididymal sperm were collected from the transgenerational F3 generation control and exposure lineage male rats for histone analysis. A reproducible core of histone H3 retention sites was observed using an H3 chromatin immunoprecipitation (ChIP-Seq) analysis in control lineage sperm. Interestingly, the same core group of H3 retention sites plus additional differential histone retention sites (DHRs) were observed in the F3 generation exposure lineage sperm. Although new histone H3 retention sites were observed, negligible change in histone modification (methylation of H3K27me3) was observed between the control and exposure lineages. Observations demonstrate that in addition to alterations in sperm DNA methylation and ncRNA previously identified, the induction of differential histone retention sites (DHRs) also appear to be involved in environmentally induced epigenetic transgenerational inheritance.

Non-infective occupational risk factors for hepatocellular carcinoma: A review

PubMed Central

Ledda, Caterina; Loreto, Carla; Zammit, Christian; Marconi, Andrea; Fago, Lucrezia; Matera, Serena; Costanzo, Valentina; Sanzà, Giovanni Fuccio; Palmucci, Stefano; Ferrante, Margherita; Costa, Chiara; Fenga, Concettina; Biondi, Antonio; Pomara, Cristoforo; Rapisarda, Venerando

2017-01-01

Liver cancer is the second leading worldwide cause of cancer-associated mortalities. Hepatocellular carcinoma, which accounts for the majority of liver tumors, ranks fifth among types of human cancer. Well-established risk factors for liver cancer include the hepatitis B and C viruses, aflatoxins, alcohol consumption, and oral contraceptives. Tobacco smoking, androgenic steroids, and diabetes mellitus are suspected risk factors. Current knowledge regarding non-infective occupational risk factors for liver cancer is inconclusive. The relevance of liver disorders to occupational medicine lies in the fact that the majority of chemicals are metabolized in the liver, and toxic metabolites generated via metabolism are the predominant cause of liver damage. However, their non-specific clinical manifestations that are similar in a number of liver diseases make diagnosis difficult. Furthermore, concomitant conditions, such as viral hepatitis and alcohol or drug abuse, may mask liver disorders that result from occupational hepatotoxic agents and block the demonstration of an occupational cause. The identification of environmental agents that result in human cancer is a long and often difficult process. The purpose of the present review is to summarize current knowledge regarding the association of non-infective occupational risk exposure and HCC, to encourage further research and draw attention to this global occupational public health problem. PMID:28000892

A histone-mimicking interdomain linker in a multidomain protein modulates multivalent histone binding

PubMed Central

Kostrhon, Sebastian; Kontaxis, Georg; Kaufmann, Tanja; Schirghuber, Erika; Kubicek, Stefan; Konrat, Robert

2017-01-01

N-terminal histone tails are subject to many posttranslational modifications that are recognized by and interact with designated reader domains in histone-binding proteins. BROMO domain adjacent to zinc finger 2B (BAZ2B) is a multidomain histone-binding protein that contains two histone reader modules, a plant homeodomain (PHD) and a bromodomain (BRD), linked by a largely disordered linker. Although previous studies have reported specificity of the PHD domain for the unmodified N terminus of histone H3 and of the BRD domain for H3 acetylated at Lys14 (H3K14ac), the exact mode of H3 binding by BAZ2B and its regulation are underexplored. Here, using isothermal titration calorimetry and NMR spectroscopy, we report that acidic residues in the BAZ2B PHD domain are essential for H3 binding and that BAZ2B PHD–BRD establishes a polyvalent interaction with H3K14ac. Furthermore, we provide evidence that the disordered interdomain linker modulates the histone-binding affinity by interacting with the PHD domain. In particular, lysine-rich stretches in the linker, which resemble the positively charged N terminus of histone H3, reduce the binding affinity of the PHD finger toward the histone substrate. Phosphorylation, acetylation, or poly(ADP-ribosyl)ation of the linker residues may therefore act as a cellular mechanism to transiently tune BAZ2B histone-binding affinity. Our findings further support the concept of interdomain linkers serving a dual role in substrate binding by appropriately positioning the adjacent domains and by electrostatically modulating substrate binding. Moreover, inhibition of histone binding by a histone-mimicking interdomain linker represents another example of regulation of protein–protein interactions by intramolecular mimicry. PMID:28864776

Histone and RNA-binding protein interaction creates crosstalk network for regulation of alternative splicing.

PubMed

Kim, Yong-Eun; Park, Chungoo; Kim, Kyoon Eon; Kim, Kee K

2018-04-30

Alternative splicing is an essential process in eukaryotes, as it increases the complexity of gene expression by generating multiple proteins from a single pre-mRNA. However, information on the regulatory mechanisms for alternative splicing is lacking, because splicing occurs over a short period via the transient interactions of proteins within functional complexes of the spliceosome. Here, we investigated in detail the molecular mechanisms connecting alternative splicing with epigenetic mechanisms. We identified interactions between histone proteins and splicing factors such as Rbfox2, Rbfox3, and splicing factor proline and glutamine rich protein (SFPQ) by in vivo crosslinking and immunoprecipitation. Furthermore, we confirmed that splicing factors were bound to specific modified residues of histone proteins. Additionally, changes in histone methylation due to histone methyltransferase inhibitor treatment notably affected alternative splicing in selected genes. Therefore, we suggested that there may be crosstalk mechanisms connecting histone modifications and RNA-binding proteins that increase the local concentration of RNA-binding proteins in alternative exon loci of nucleosomes by binding specific modified histone proteins, leading to alternative splicing. This crosstalk mechanism may play a major role in epigenetic processes such as histone modification and the regulation of alternative splicing. Copyright © 2018 Elsevier Inc. All rights reserved.

Role of novel histone modifications in cancer

PubMed Central

Shanmugam, Muthu K.; Arfuso, Frank; Arumugam, Surendar; Chinnathambi, Arunachalam; Jinsong, Bian; Warrier, Sudha; Wang, Ling Zhi; Kumar, Alan Prem; Ahn, Kwang Seok; Sethi, Gautam; Lakshmanan, Manikandan

2018-01-01

Oncogenesis is a multistep process mediated by a variety of factors including epigenetic modifications. Global epigenetic post-translational modifications have been detected in almost all cancers types. Epigenetic changes appear briefly and do not involve permanent changes to the primary DNA sequence. These epigenetic modifications occur in key oncogenes, tumor suppressor genes, and transcription factors, leading to cancer initiation and progression. The most commonly observed epigenetic changes include DNA methylation, histone lysine methylation and demethylation, histone lysine acetylation and deacetylation. However, there are several other novel post-translational modifications that have been observed in recent times such as neddylation, sumoylation, glycosylation, phosphorylation, poly-ADP ribosylation, ubiquitination as well as transcriptional regulation and these have been briefly discussed in this article. We have also highlighted the diverse epigenetic changes that occur during the process of tumorigenesis and described the role of histone modifications that can occur on tumor suppressor genes as well as oncogenes, which regulate tumorigenesis and can thus form the basis of novel strategies for cancer therapy. PMID:29541423

Zinc finger transcription factor CASZ1 interacts with histones, DNA repair proteins and recruits NuRD complex to regulate gene transcription.

PubMed

Liu, Zhihui; Lam, Norris; Thiele, Carol J

2015-09-29

The zinc finger transcription factor CASZ1 has been found to control neural fate-determination in flies, regulate murine and frog cardiac development, control murine retinal cell progenitor expansion and function as a tumor suppressor gene in humans. However, the molecular mechanism by which CASZ1 regulates gene transcription to exert these diverse biological functions has not been described. Here we identify co-factors that are recruited by CASZ1b to regulate gene transcription using co-immunoprecipitation (co-IP) and mass spectrometry assays. We find that CASZ1b binds to the nucleosome remodeling and histone deacetylase (NuRD) complex, histones and DNA repair proteins. Mutagenesis of the CASZ1b protein assay demonstrates that the N-terminus of CASZ1b is required for NuRD binding, and a poly(ADP-ribose) binding motif in the CASZ1b protein is required for histone H3 and DNA repair proteins binding. The N-terminus of CASZ1b fused to an artificial DNA-binding domain (GAL4DBD) causes a significant repression of transcription (5xUAS-luciferase assay), which could be blocked by treatment with an HDAC inhibitor. Realtime PCR results show that the transcriptional activity of CASZ1b mutants that abrogate NuRD or histone H3/DNA binding is significantly decreased. This indicates a model in which CASZ1b binds to chromatin and recruits NuRD complexes to orchestrate epigenetic-mediated transcriptional programs.

Retinoic acids and trichostatin A (TSA), a histone deacetylase inhibitor, induce human pyruvate dehydrogenase kinase 4 (PDK4) gene expression.

PubMed

Kwon, Hye-Sook; Huang, Boli; Ho Jeoung, Nam; Wu, Pengfei; Steussy, Calvin N; Harris, Robert A

2006-01-01

Induction of pyruvate dehydrogenase kinase 4 (PDK4) conserves glucose and substrates for gluconeogenesis and thereby helps regulate blood glucose levels during starvation. We report here that retinoic acids (RA) as well as Trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC), regulate PDK4 gene expression. Two retinoic acid response elements (RAREs) to which retinoid X receptor alpha (RXRalpha) and retinoic acid receptor alpha (RARalpha) bind and activate transcription are present in the human PDK4 (hPDK4) proximal promoter. Sp1 and CCAAT box binding factor (CBF) bind to the region between two RAREs. Mutation of either the Sp1 or the CBF site significantly decreases basal expression, transactivation by RXRalpha/RARalpha/RA, and the ability of TSA to stimulate hPDK4 gene transcription. By the chromatin immunoprecipitation assay, RA and TSA increase acetylation of histones bound to the proximal promoter as well as occupancy of CBP and Sp1. Interaction of p300/CBP with E1A completely prevented hPDK4 gene activation by RXRalpha/RARalpha/RA and TSA. The p300/CBP may enhance acetylation of histones bound to the hPDK4 promoter and cooperate with Sp1 and CBF to stimulate transcription of the hPDK4 gene in response to RA and TSA.

[Editorial] Environmental and occupational risk factors associated with different pathological conditions.

PubMed

Signorelli, Salvatore Santo; Ferrante, Margherita

2017-05-01

A wide body of evidence indicates that environmental and occupational risk factors are associated with the development of pathological disorders. The pathogenic role of many environmental pollutants or occupational contaminants is already known and has been extensively investigated. However, the molecular mechanisms of action and the pathogenic effects of many substances remain unknown. Therefore, there is a need to better investigate the role of new environmental and occupational risk factors that may cause the development of several diseases.

Role of Histone Acetylation in the Assembly and Modulation of Chromatin Structures

PubMed Central

Annunziato, Anthony T.; Hansen, Jeffrey C.

2000-01-01

The acetylation of the core histone N-terminal “tail” domains is now recognized as a highly conserved mechanism for regulating chromatin functional states. The following article examines possible roles of acetylation in two critically important cellular processes: replication-coupled nucleosome assembly, and reversible transitions in chromatin higher order structure. After a description of the acetylation of newly synthesized histones, and of the likely acetyltransferases involved, an overview of histone octamer assembly is presented. Our current understanding of the factors thought to assemble chromatin in vivo is then described. Genetic and biochemical investigations of the function the histone tails, and their acetylation, in nucleosome assembly are detailed, followed by an analysis of the importance of histone deacetylation in the maturation of newly replicated chromatin. In the final section the involvement of the histone tail domains in chromatin higher order structures is addressed, along with the role of histone acetylation in chromatin folding. Suggestions for future research are offered in the concluding remarks. PMID:11097424

A mechanism for histone chaperoning activity of nucleoplasmin: thermodynamic and structural models.

PubMed

Taneva, Stefka G; Bañuelos, Sonia; Falces, Jorge; Arregi, Igor; Muga, Arturo; Konarev, Petr V; Svergun, Dmitri I; Velázquez-Campoy, Adrián; Urbaneja, María A

2009-10-23

Nucleoplasmin (NP), a histone chaperone, acts as a reservoir for histones H2A-H2B in Xenopus laevis eggs and can displace sperm nuclear basic proteins and linker histones from the chromatin fiber of sperm and quiescent somatic nuclei. NP has been proposed to mediate the dynamic exchange of histones during the expression of certain genes and assists the assembly of nucleosomes by modulating the interaction between histones and DNA. Here, solution structural models of full-length NP and NP complexes with the functionally distinct nucleosomal core and linker histones are presented for the first time, providing a picture of the physical interactions between the nucleosomal and linker histones with NP core and tail domains. Small-angle X-ray scattering and isothermal titration calorimetry reveal that NP pentamer can accommodate five histones, either H2A-H2B dimers or H5, and that NP core and tail domains are intimately involved in the association with histones. The analysis of the binding events, employing a site-specific cooperative model, reveals a negative cooperativity-based regulatory mechanism for the linker histone/nucleosomal histone exchange. The two histone types bind with drastically different intrinsic affinity, and the strongest affinity is observed for the NP variant that mimicks the hyperphosphorylated active protein. The different "affinity windows" for H5 and H2A-H2B might allow NP to fulfill its histone chaperone role, simultaneously acting as a reservoir for the core histones and a chromatin decondensing factor. Our data are compatible with the previously proposed model where NP facilitates nucleosome assembly by removing the linker histones and depositing H2A-H2B dimers onto DNA.

Carpal tunnel syndrome: the role of occupational factors.

PubMed

Palmer, Keith T

2011-02-01

Carpal tunnel syndrome (CTS) is a fairly common condition in working-aged people, sometimes caused by physical occupational activities, such as repeated and forceful movements of the hand and wrist or use of hand-held, powered, vibratory tools. Symptoms may be prevented or alleviated by primary control measures at work, and some cases of disease are compensable. Following a general description of the disorder, its epidemiology and some of the difficulties surrounding diagnosis, this review focusses on the role of occupational factors in causation of CTS and factors that can mitigate risk. Areas of uncertainty, debate and research interest are emphasised where relevant. Copyright © 2011 Elsevier Ltd. All rights reserved.

Hand pain other than carpal tunnel syndrome (CTS): the role of occupational factors.

PubMed

Andréu, José-Luis; Otón, Teresa; Silva-Fernández, Lucía; Sanz, Jesús

2011-02-01

Some occupational factors have been implicated in the development of disorders manifested as hand pain. The associations seem to be well documented in processes such as hand-arm vibration syndrome (HAVS) or writer's cramp. There are contradictory data in the literature about the relationships of trigger finger, De Quervain's tenosynovitis (DQT) and tenosynovitis of the wrist with occupational factors. In this article, we review current knowledge about clinical manifestations, case definition, implicated occupational factors, diagnosis and treatment of the most relevant hand pain disorders that have been associated with occupational factors, excluding carpal tunnel syndrome (CTS). Copyright © 2010 Elsevier Ltd. All rights reserved.

Replication-Independent Histone Deposition by the HIR Complex and Asf1

PubMed Central

Green, Erin M.; Antczak, Andrew J.; Bailey, Aaron O.; Franco, Alexa A.; Wu, Kevin J.; Yates, John R.; Kaufman, Paul D.

2010-01-01

Summary The orderly deposition of histones onto DNA is mediated by conserved assembly complexes, including Chromatin Assembly Factor-1 (CAF-1) and the Hir proteins [1–4]. CAF-1 and the Hir proteins operate in distinct but functionally overlapping histone deposition pathways in vivo [5, 6]. The Hir proteins and CAF-1 share a common partner, the highly conserved histone H3/H4-binding protein Asf1, which binds the middle subunit of CAF-1 as well as to Hir proteins [7–11]. Asf1 binds to newly synthesized histones H3/H4 [12] and this complex stimulates histone deposition by CAF-1 [7, 12, 13]. In yeast, Asf1 is required for the contribution of the Hir proteins to gene silencing [7, 14]. Here, we demonstrate that Hir1, Hir2, Hir3 and Hpc2 comprise the HIR complex, which co-purifies with histone deposition protein Asf1. Together, the HIR complex and Asf1 deposit histones onto DNA in a replication-independent manner. Histone deposition by the HIR complex and Asf1 is impaired by a mutation in Asf1 that inhibits HIR binding. These data indicate that the HIR complex and Asf1 proteins function together as a conserved eukaryotic pathway for histone replacement throughout the cell cycle. PMID:16303565

Factors influencing subjective perceptions of everyday occupations: comparing day centre attendees with non-attendees.

PubMed

Argentzell, Elisabeth; Leufstadius, Christel; Eklund, Mona

2012-01-01

Subjective perceptions of everyday occupations are important for the well-being of people with psychiatric disabilities (PD) and are likely to vary with factors such as attending a day centre or not, activity level, self-mastery, sociodemographic and clinical factors. To explore differences in subjective perceptions of occupation and activity level between day centre attendees and non-attendees, and to investigate factors of importance for the subjective perceptions of occupations. The study groups comprised 175 participants: 93 day centre attendees and 82 non-attendees. Data were collected with instruments concerning; subjective perceptions of everyday occupations, activity level, self-mastery, and sociodemographic and clinical factors. Day centre attendees perceived higher levels of occupational value and activity level, while the groups perceived a similar level of satisfaction with daily occupations. For the total sample, self-mastery influenced both valued and satisfying everyday occupations while only value was affected by activity level. Satisfaction with daily occupation increased with age and both value and satisfaction increased with lower levels of psychiatric symptoms. Day centres provide perceptions of occupational value and stimulate activity. Non-differences between the groups regarding satisfaction with everyday occupations implied, however, that day centres might not cover all relevant occupational needs.

Occupational risk factors for Parkinson's disease: a case-control study in Japan

PubMed Central

2011-01-01

Background The evidence for associations between occupational factors and the risk of Parkinson's disease (PD) is inconsistent. We assessed the risk of PD associated with various occupational factors in Japan. Methods We examined 249 cases within 6 years of onset of PD. Control subjects were 369 inpatients and outpatients without neurodegenerative disease. Information on occupational factors was obtained from a self-administered questionnaire. Relative risks of PD were estimated using odds ratios (ORs) and 95% confidence intervals (CIs) based on logistic regression. Adjustments were made for gender, age, region of residence, educational level, and pack-years of smoking. Results Working in a professional or technical occupation tended to be inversely related to the risk of PD: adjusted OR was 0.59 (95% CI: 0.32-1.06, P = 0.08). According to a stratified analysis by gender, the decreased risk of PD for persons in professional or technical occupations was statistically significant only for men. Adjusted ORs for a professional or technical occupation among men and women were 0.22 (95% CI: 0.06-0.67) and 0.99 (0.47-2.07), respectively, and significant interaction was observed (P = 0.048 for homogeneity of OR). In contrast, risk estimates for protective service occupations and transport or communications were increased, although the results were not statistically significant: adjusted ORs were 2.73 (95% CI: 0.56-14.86) and 1.74 (95% CI: 0.65-4.74), respectively. No statistical significance was seen in data concerning exposure to occupational agents and the risk of PD, although roughly a 2-fold increase in OR was observed for workers exposed to stone or sand. Conclusion The results of our study suggest that occupational factors do not play a substantial etiologic role in this population. However, among men, professional or technical occupations may decrease the risk of PD. PMID:21733194

Risk factors of fatal occupational accidents in Iran.

PubMed

Asady, Hadi; Yaseri, Mehdi; Hosseini, Mostafa; Zarif-Yeganeh, Morvarid; Yousefifard, Mahmoud; Haghshenas, Mahin; Hajizadeh-Moghadam, Parisa

2018-01-01

Occupational accidents are of most important consequences of globalization in developing countries. Therefore, investigating the causes of occupational accidents for improving the job situation and making operational policy is necessary. So the aim of this study was to investigate factors affecting the fatal occupational accidents and also calculate the years of life lost for dead workers. This cross-sectional study was conducted on data related to the 6052 injured workers that was registered in the 2013 registry system of the Ministry of Health and Medical Education of Iran. Variables including sex, education, age, job tenure, injury cause, referred location of injured workers, occupation, shift work, season, accident day, damaged part of the body were chosen as independent variables. The Chi-squared and Fisher exact tests were used for univariate analysis and then exact multiple logistic regression was carried out to identify independent risk factors of fatal occupational accidents. Finally, for dead workers, years of life lost, according to the injury causes was calculated. Among the 6052 accidents reported, 33 deaths were recorded. Chi-square and Fisher exact tests showed that factors including: current job tenure ( p  = 0.01), damaged parts of the body ( p  < 0.001) and injury cause ( p  < 0.001) are associated with the fatal accidents. Also exact multiple logistic regression analysis showed a significant association between electric shocks as a cause of injury (OR = 7.04; 95% CI: 1.01-43.74; p  = 0.02) and current job tenure more than 1 year (OR = 0.21; 95% CI: 0.05-0.70; p  = 0.005) with the fatal accidents. The total amount of years of life lost based on causes of injuries was estimated 1289.12 years. In Iran, fatal accident odds in workers with job tenure more than 1 year was less in comparing to the workers with job tenure less and equal to 1 year. Also odd of death for electrical shock was more than other causes of injuries. So it seems

Histone Lysine Methylation and Neurodevelopmental Disorders.

PubMed

Kim, Jeong-Hoon; Lee, Jang Ho; Lee, Im-Soon; Lee, Sung Bae; Cho, Kyoung Sang

2017-06-30

Methylation of several lysine residues of histones is a crucial mechanism for relatively long-term regulation of genomic activity. Recent molecular biological studies have demonstrated that the function of histone methylation is more diverse and complex than previously thought. Moreover, studies using newly available genomics techniques, such as exome sequencing, have identified an increasing number of histone lysine methylation-related genes as intellectual disability-associated genes, which highlights the importance of accurate control of histone methylation during neurogenesis. However, given the functional diversity and complexity of histone methylation within the cell, the study of the molecular basis of histone methylation-related neurodevelopmental disorders is currently still in its infancy. Here, we review the latest studies that revealed the pathological implications of alterations in histone methylation status in the context of various neurodevelopmental disorders and propose possible therapeutic application of epigenetic compounds regulating histone methylation status for the treatment of these diseases.

A brief histone in time: understanding the combinatorial functions of histone PTMs in the nucleosome context.

PubMed

Ng, Marlee K; Cheung, Peter

2016-02-01

It has been over 50 years since Allfrey et al. proposed that histone acetylation regulates RNA synthesis, and the study of histone modifications has progressed at an extraordinary pace for the past two decades. In this review, we provide a perspective on some key events and advances in our understanding of histone modifications. We also highlight reagents and tools from past to present that facilitated progress in this research field. Using histone H3 phosphorylation as an underlying thread, we review the rationale that led to the proposal of the histone code hypothesis, as well as examples that illustrate the concepts of combinatorial histone modifications and cross-talk pathways. We further highlight the importance of investigating these mechanisms in the context of nucleosomes rather than just at the histone level and present current and developing approaches for such studies. Overall, research on histone modifications has yielded great mechanistic insights into the regulation of genomic functions, and extending these studies using nucleosomes will further elucidate the complexity of these pathways in a more physiologically relevant context.

Loss of epigenetic Kruppel-like factor 4 histone deacetylase (KLF-4-HDAC)-mediated transcriptional suppression is crucial in increasing vascular endothelial growth factor (VEGF) expression in breast cancer.

PubMed

Ray, Alpana; Alalem, Mohamed; Ray, Bimal K

2013-09-20

Vascular endothelial growth factor (VEGF) is recognized as an important angiogenic factor that promotes angiogenesis in a series of pathological conditions, including cancer, inflammation, and ischemic disorders. We have recently shown that the inflammatory transcription factor SAF-1 is, at least in part, responsible for the marked increase of VEGF levels in breast cancer. Here, we show that SAF-1-mediated induction of VEGF is repressed by KLF-4 transcription factor. KLF-4 is abundantly present in normal breast epithelial cells, but its level is considerably reduced in breast cancer cells and clinical cancer tissues. In the human VEGF promoter, SAF-1- and KLF-4-binding elements are overlapping, whereas SAF-1 induces and KLF-4 suppresses VEGF expression. Ectopic overexpression of KLF-4 and RNAi-mediated inhibition of endogenous KLF-4 supported the role of KLF-4 as a transcriptional repressor of VEGF and an inhibitor of angiogenesis in breast cancer cells. We show that KLF-4 recruits histone deacetylases (HDACs) -2 and -3 at the VEGF promoter. Chronological ChIP assays demonstrated the occupancy of KLF-4, HDAC2, and HDAC3 in the VEGF promoter in normal MCF-10A cells but not in MDA-MB-231 cancer cells. Co-transfection of KLF-4 and HDAC expression plasmids in breast cancer cells results in synergistic repression of VEGF expression and inhibition of angiogenic potential of these carcinoma cells. Together these results identify a new mechanism of VEGF up-regulation in cancer that involves concomitant loss of KLF-4-HDAC-mediated transcriptional repression and active recruitment of SAF-1-mediated transcriptional activation.

One-pot refolding of core histones from bacterial inclusion bodies allows rapid reconstitution of histone octamer.

PubMed

Lee, Young-Tae; Gibbons, Garrett; Lee, Shirley Y; Nikolovska-Coleska, Zaneta; Dou, Yali

2015-06-01

We report an optimized method to purify and reconstitute histone octamer, which utilizes high expression of histones in inclusion bodies but eliminates the time consuming steps of individual histone purification. In the newly modified protocol, Xenopus laevis H2A, H2B, H3, and H4 are expressed individually into inclusion bodies of bacteria, which are subsequently mixed together and denatured in 8M guanidine hydrochloride. Histones are refolded and reconstituted into soluble octamer by dialysis against 2M NaCl, and metal-affinity purified through an N-terminal polyhistidine-tag added on the H2A. After cleavage of the polyhistidine-tag, histone octamer is further purified by size exclusion chromatography. We show that the nucleosomes reconstituted using the purified histone octamer above are fully functional. They serve as effective substrates for the histone methyltransferases DOT1L and MLL1. Small angle X-ray scattering further confirms that the reconstituted nucleosomes have correct structural integration of histone octamer and DNA as observed in the X-ray crystal structure. Our new protocol enables rapid reconstitution of histone octamer with an optimal yield. We expect this simplified approach to facilitate research using recombinant nucleosomes in vitro. Copyright © 2015 Elsevier Inc. All rights reserved.

Factors associated with occupational exposure to biological material among nursing professionals.

PubMed

Negrinho, Nádia Bruna da Silva; Malaguti-Toffano, Silmara Elaine; Reis, Renata Karina; Pereira, Fernanda Maria Vieira; Gir, Elucir

2017-01-01

to identify factors associated with occupational exposure to biological material among nursing professionals. a cross-sectional study was conducted in a high complexity hospital of a city in the state of São Paulo, Brazil. Nursing professionals were interviewed from March to November 2015. All ethical aspects were observed. among the 226 professionals interviewed, 17.3% suffered occupational exposure to potentially contaminated biological material, with 61.5% being percutaneous. Factors such as age (p=0.003), professional experience in nursing (p=0.015), and experience at the institution (p=0.032) were associated with the accidents with biological material. most accidents with biological material among nursing professionals were percutaneous. Age, professional experience, and experience at the institution were considered factors associated with occupational exposure.

A Common histone modification code on C4 genes in maize and its conservation in Sorghum and Setaria italica.

PubMed

Heimann, Louisa; Horst, Ina; Perduns, Renke; Dreesen, Björn; Offermann, Sascha; Peterhansel, Christoph

2013-05-01

C4 photosynthesis evolved more than 60 times independently in different plant lineages. Each time, multiple genes were recruited into C4 metabolism. The corresponding promoters acquired new regulatory features such as high expression, light induction, or cell type-specific expression in mesophyll or bundle sheath cells. We have previously shown that histone modifications contribute to the regulation of the model C4 phosphoenolpyruvate carboxylase (C4-Pepc) promoter in maize (Zea mays). We here tested the light- and cell type-specific responses of three selected histone acetylations and two histone methylations on five additional C4 genes (C4-Ca, C4-Ppdk, C4-Me, C4-Pepck, and C4-RbcS2) in maize. Histone acetylation and nucleosome occupancy assays indicated extended promoter regions with regulatory upstream regions more than 1,000 bp from the transcription initiation site for most of these genes. Despite any detectable homology of the promoters on the primary sequence level, histone modification patterns were highly coregulated. Specifically, H3K9ac was regulated by illumination, whereas H3K4me3 was regulated in a cell type-specific manner. We further compared histone modifications on the C4-Pepc and C4-Me genes from maize and the homologous genes from sorghum (Sorghum bicolor) and Setaria italica. Whereas sorghum and maize share a common C4 origin, C4 metabolism evolved independently in S. italica. The distribution of histone modifications over the promoters differed between the species, but differential regulation of light-induced histone acetylation and cell type-specific histone methylation were evident in all three species. We propose that a preexisting histone code was recruited into C4 promoter control during the evolution of C4 metabolism.

Epigenetic control of skull morphogenesis by histone deacetylase 8

PubMed Central

Haberland, Michael; Mokalled, Mayssa H.; Montgomery, Rusty L.; Olson, Eric N.

2009-01-01

Histone deacetylases (Hdacs) are transcriptional repressors with crucial roles in mammalian development. Here we provide evidence that Hdac8 specifically controls patterning of the skull by repressing a subset of transcription factors in cranial neural crest cells. Global deletion of Hdac8 in mice leads to perinatal lethality due to skull instability, and this is phenocopied by conditional deletion of Hdac8 in cranial neural crest cells. Hdac8 specifically represses the aberrant expression of homeobox transcription factors such as Otx2 and Lhx1. These findings reveal how the identity and patterning of vertebrate-specific portions of the skull are epigenetically controlled by a histone deacetylase. PMID:19605684

Solar Simulated Ultraviolet Radiation Induces Global Histone Hypoacetylation in Human Keratinocytes.

PubMed

Zhang, Xiaoru; Kluz, Thomas; Gesumaria, Lisa; Matsui, Mary S; Costa, Max; Sun, Hong

2016-01-01

Ultraviolet radiation (UVR) from sunlight is the primary effector of skin DNA damage. Chromatin remodeling and histone post-translational modification (PTM) are critical factors in repairing DNA damage and maintaining genomic integrity, however, the dynamic changes of histone marks in response to solar UVR are not well characterized. Here we report global changes in histone PTMs induced by solar simulated UVR (ssUVR). A decrease in lysine acetylation of histones H3 and H4, particularly at positions of H3 lysine 9, lysine 56, H4 lysine 5, and lysine 16, was found in human keratinocytes exposed to ssUVR. These acetylation changes were highly associated with ssUVR in a dose-dependent and time-specific manner. Interestingly, H4K16ac, a mark that is crucial for higher order chromatin structure, exhibited a persistent reduction by ssUVR that was transmitted through multiple cell divisions. In addition, the enzymatic activities of histone acetyltransferases were significantly reduced in irradiated cells, which may account for decreased global acetylation. Moreover, depletion of histone deacetylase SIRT1 in keratinocytes rescued ssUVR-induced H4K16 hypoacetylation. These results indicate that ssUVR affects both HDAC and HAT activities, leading to reduced histone acetylation.

Solar Simulated Ultraviolet Radiation Induces Global Histone Hypoacetylation in Human Keratinocytes

PubMed Central

Zhang, Xiaoru; Kluz, Thomas; Gesumaria, Lisa; Matsui, Mary S.; Costa, Max; Sun, Hong

2016-01-01

Ultraviolet radiation (UVR) from sunlight is the primary effector of skin DNA damage. Chromatin remodeling and histone post-translational modification (PTM) are critical factors in repairing DNA damage and maintaining genomic integrity, however, the dynamic changes of histone marks in response to solar UVR are not well characterized. Here we report global changes in histone PTMs induced by solar simulated UVR (ssUVR). A decrease in lysine acetylation of histones H3 and H4, particularly at positions of H3 lysine 9, lysine 56, H4 lysine 5, and lysine 16, was found in human keratinocytes exposed to ssUVR. These acetylation changes were highly associated with ssUVR in a dose-dependent and time-specific manner. Interestingly, H4K16ac, a mark that is crucial for higher order chromatin structure, exhibited a persistent reduction by ssUVR that was transmitted through multiple cell divisions. In addition, the enzymatic activities of histone acetyltransferases were significantly reduced in irradiated cells, which may account for decreased global acetylation. Moreover, depletion of histone deacetylase SIRT1 in keratinocytes rescued ssUVR-induced H4K16 hypoacetylation. These results indicate that ssUVR affects both HDAC and HAT activities, leading to reduced histone acetylation. PMID:26918332

The Scientific Basis of Uncertainty Factors Used in Setting Occupational Exposure Limits.

PubMed

Dankovic, D A; Naumann, B D; Maier, A; Dourson, M L; Levy, L S

2015-01-01

The uncertainty factor concept is integrated into health risk assessments for all aspects of public health practice, including by most organizations that derive occupational exposure limits. The use of uncertainty factors is predicated on the assumption that a sufficient reduction in exposure from those at the boundary for the onset of adverse effects will yield a safe exposure level for at least the great majority of the exposed population, including vulnerable subgroups. There are differences in the application of the uncertainty factor approach among groups that conduct occupational assessments; however, there are common areas of uncertainty which are considered by all or nearly all occupational exposure limit-setting organizations. Five key uncertainties that are often examined include interspecies variability in response when extrapolating from animal studies to humans, response variability in humans, uncertainty in estimating a no-effect level from a dose where effects were observed, extrapolation from shorter duration studies to a full life-time exposure, and other insufficiencies in the overall health effects database indicating that the most sensitive adverse effect may not have been evaluated. In addition, a modifying factor is used by some organizations to account for other remaining uncertainties-typically related to exposure scenarios or accounting for the interplay among the five areas noted above. Consideration of uncertainties in occupational exposure limit derivation is a systematic process whereby the factors applied are not arbitrary, although they are mathematically imprecise. As the scientific basis for uncertainty factor application has improved, default uncertainty factors are now used only in the absence of chemical-specific data, and the trend is to replace them with chemical-specific adjustment factors whenever possible. The increased application of scientific data in the development of uncertainty factors for individual chemicals also has

Nitric Oxide Modulates Histone Acetylation at Stress Genes by Inhibition of Histone Deacetylases.

PubMed

Mengel, Alexander; Ageeva, Alexandra; Georgii, Elisabeth; Bernhardt, Jörg; Wu, Keqiang; Durner, Jörg; Lindermayr, Christian

2017-02-01

Histone acetylation, which is an important mechanism to regulate gene expression, is controlled by the opposing action of histone acetyltransferases and histone deacetylases (HDACs). In animals, several HDACs are subjected to regulation by nitric oxide (NO); in plants, however, it is unknown whether NO affects histone acetylation. We found that treatment with the physiological NO donor S-nitrosoglutathione (GSNO) increased the abundance of several histone acetylation marks in Arabidopsis (Arabidopsis thaliana), which was strongly diminished in the presence of the NO scavenger 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. This increase was likely triggered by NO-dependent inhibition of HDAC activity, since GSNO and S-nitroso-N-acetyl-dl-penicillamine significantly and reversibly reduced total HDAC activity in vitro (in nuclear extracts) and in vivo (in protoplasts). Next, genome-wide H3K9/14ac profiles in Arabidopsis seedlings were generated by chromatin immunoprecipitation sequencing, and changes induced by GSNO, GSNO/2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide or trichostatin A (an HDAC inhibitor) were quantified, thereby identifying genes that display putative NO-regulated histone acetylation. Functional classification of these genes revealed that many of them are involved in the plant defense response and the abiotic stress response. Furthermore, salicylic acid, which is the major plant defense hormone against biotrophic pathogens, inhibited HDAC activity and increased histone acetylation by inducing endogenous NO production. These data suggest that NO affects histone acetylation by targeting and inhibiting HDAC complexes, resulting in the hyperacetylation of specific genes. This mechanism might operate in the plant stress response by facilitating the stress-induced transcription of genes. © 2017 American Society of Plant Biologists. All Rights Reserved.

Diversity and Divergence of Dinoflagellate Histone Proteins

PubMed Central

Marinov, Georgi K.; Lynch, Michael

2015-01-01

Histone proteins and the nucleosomal organization of chromatin are near-universal eukaroytic features, with the exception of dinoflagellates. Previous studies have suggested that histones do not play a major role in the packaging of dinoflagellate genomes, although several genomic and transcriptomic surveys have detected a full set of core histone genes. Here, transcriptomic and genomic sequence data from multiple dinoflagellate lineages are analyzed, and the diversity of histone proteins and their variants characterized, with particular focus on their potential post-translational modifications and the conservation of the histone code. In addition, the set of putative epigenetic mark readers and writers, chromatin remodelers and histone chaperones are examined. Dinoflagellates clearly express the most derived set of histones among all autonomous eukaryote nuclei, consistent with a combination of relaxation of sequence constraints imposed by the histone code and the presence of numerous specialized histone variants. The histone code itself appears to have diverged significantly in some of its components, yet others are conserved, implying conservation of the associated biochemical processes. Specifically, and with major implications for the function of histones in dinoflagellates, the results presented here strongly suggest that transcription through nucleosomal arrays happens in dinoflagellates. Finally, the plausible roles of histones in dinoflagellate nuclei are discussed. PMID:26646152

The histone modifications governing TFF1 transcription mediated by estrogen receptor.

PubMed

Li, Yanyan; Sun, Luyang; Zhang, Yu; Wang, Dandan; Wang, Feng; Liang, Jing; Gui, Bin; Shang, Yongfeng

2011-04-22

Transcription regulation by histone modifications is a major contributing factor to the structural and functional diversity in biology. These modifications are encrypted as histone codes or histone languages and function to establish and maintain heritable epigenetic codes that define the identity and the fate of the cell. Despite recent advances revealing numerous histone modifications associated with transcription regulation, how such modifications dictate the process of transcription is not fully understood. Here we describe spatial and temporal analyses of the histone modifications that are introduced during estrogen receptor α (ERα)-activated transcription. We demonstrated that aborting RNA polymerase II caused a disruption of the histone modifications that are associated with transcription elongation but had a minimal effect on modifications deposited during transcription initiation. We also found that the histone H3S10 phosphorylation mark is catalyzed by mitogen- and stress-activated protein kinase 1 (MSK1) and is recognized by a 14-3-3ζ/14-3-3ε heterodimer through its interaction with H3K4 trimethyltransferase SMYD3 and the p52 subunit of TFIIH. We showed that H3S10 phosphorylation is a prerequisite for H3K4 trimethylation. In addition, we demonstrated that SET8/PR-Set7/KMT5A is required for ERα-regulated transcription and its catalyzed H4K20 monomethylation is implicated in both transcription initiation and elongation. Our experiments provide a relatively comprehensive analysis of histone modifications associated with ERα-regulated transcription and define the biological meaning of several key components of the histone code that governs ERα-regulated transcription.

Factors Associated with Fatal Occupational Accidents among Mexican Workers: A National Analysis

PubMed Central

Gonzalez-Delgado, Mery; Gómez-Dantés, Héctor; Fernández-Niño, Julián Alfredo; Robles, Eduardo; Borja, Víctor H.; Aguilar, Miriam

2015-01-01

Objective To identify the factors associated with fatal occupational injuries in Mexico in 2012 among workers affiliated with the Mexican Social Security Institute. Methods Analysis of secondary data using information from the National Occupational Risk Information System, with the consequence of the occupational injury (fatal versus non-fatal) as the response variable. The analysis included 406,222 non-fatal and 1,140 fatal injuries from 2012. The factors associated with the lethality of the injury were identified using a logistic regression model with the Firth approach. Results Being male (OR=5.86; CI95%: 4.22-8.14), age (OR=1.04; CI95%: 1.03-1.06), employed in the position for 1 to 10 years (versus less than 1 year) (OR=1.37; CI95%: 1.15-1.63), working as a facilities or machine operator or assembler (OR: 3.28; CI95%: 2.12- 5.07) and being a worker without qualifications (OR=1.96; CI95%: 1.18-3.24) (versus an office worker) were associated with fatality in the event of an injury. Additionally, companies classified as maximum risk (OR=1.90; CI 95%: 1.38-2.62), workplace conditions (OR=7.15; CI95%: 3.63-14.10) and factors related to the work environment (OR=9.18; CI95%:4.36-19.33) were identified as risk factors for fatality in the event of an occupational injury. Conclusions Fatality in the event of an occupational injury is associated with factors related to sociodemographics (age, sex and occupation), the work environment and workplace conditions. Worker protection policies should be created for groups with a higher risk of fatal occupational injuries in Mexico. PMID:25790063

Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia.

PubMed

Müller-Tidow, Carsten; Klein, Hans-Ulrich; Hascher, Antje; Isken, Fabienne; Tickenbrock, Lara; Thoennissen, Nils; Agrawal-Singh, Shuchi; Tschanter, Petra; Disselhoff, Christine; Wang, Yipeng; Becker, Anke; Thiede, Christian; Ehninger, Gerhard; zur Stadt, Udo; Koschmieder, Steffen; Seidl, Matthias; Müller, Frank U; Schmitz, Wilhelm; Schlenke, Peter; McClelland, Michael; Berdel, Wolfgang E; Dugas, Martin; Serve, Hubert

2010-11-04

Acute myeloid leukemia (AML) is commonly associated with alterations in transcription factors because of altered expression or gene mutations. These changes might induce leukemia-specific patterns of histone modifications. We used chromatin-immunoprecipitation on microarray to analyze histone 3 lysine 9 trimethylation (H3K9me3) patterns in primary AML (n = 108), acute lymphoid leukemia (n = 28), CD34(+) cells (n = 21) and white blood cells (n = 15) specimens. Hundreds of promoter regions in AML showed significant alterations in H3K9me3 levels. H3K9me3 deregulation in AML occurred preferentially as a decrease in H3K9me3 levels at core promoter regions. The altered genomic regions showed an overrepresentation of cis-binding sites for ETS and cyclic adenosine monophosphate response elements (CREs) for transcription factors of the CREB/CREM/ATF1 family. The decrease in H3K9me3 levels at CREs was associated with increased CRE-driven promoter activity in AML blasts in vivo. AML-specific H3K9me3 patterns were not associated with known cytogenetic abnormalities. But a signature derived from H3K9me3 patterns predicted event-free survival in AML patients. When the H3K9me3 signature was combined with established clinical prognostic markers, it outperformed prognosis prediction based on clinical parameters alone. These findings demonstrate widespread changes of H3K9me3 levels at gene promoters in AML. Signatures of histone modification patterns are associated with patient prognosis in AML.

Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia

PubMed Central

Klein, Hans-Ulrich; Hascher, Antje; Isken, Fabienne; Tickenbrock, Lara; Thoennissen, Nils; Agrawal-Singh, Shuchi; Tschanter, Petra; Disselhoff, Christine; Wang, Yipeng; Becker, Anke; Thiede, Christian; Ehninger, Gerhard; zur Stadt, Udo; Koschmieder, Steffen; Seidl, Matthias; Müller, Frank U.; Schmitz, Wilhelm; Schlenke, Peter; McClelland, Michael; Berdel, Wolfgang E.; Dugas, Martin; Serve, Hubert

2010-01-01

Acute myeloid leukemia (AML) is commonly associated with alterations in transcription factors because of altered expression or gene mutations. These changes might induce leukemia-specific patterns of histone modifications. We used chromatin-immunoprecipitation on microarray to analyze histone 3 lysine 9 trimethylation (H3K9me3) patterns in primary AML (n = 108), acute lymphoid leukemia (n = 28), CD34+ cells (n = 21) and white blood cells (n = 15) specimens. Hundreds of promoter regions in AML showed significant alterations in H3K9me3 levels. H3K9me3 deregulation in AML occurred preferentially as a decrease in H3K9me3 levels at core promoter regions. The altered genomic regions showed an overrepresentation of cis-binding sites for ETS and cyclic adenosine monophosphate response elements (CREs) for transcription factors of the CREB/CREM/ATF1 family. The decrease in H3K9me3 levels at CREs was associated with increased CRE-driven promoter activity in AML blasts in vivo. AML-specific H3K9me3 patterns were not associated with known cytogenetic abnormalities. But a signature derived from H3K9me3 patterns predicted event-free survival in AML patients. When the H3K9me3 signature was combined with established clinical prognostic markers, it outperformed prognosis prediction based on clinical parameters alone. These findings demonstrate widespread changes of H3K9me3 levels at gene promoters in AML. Signatures of histone modification patterns are associated with patient prognosis in AML. PMID:20498303

Interaction of Occupational and Personal Risk Factors in Workforce Health and Safety

PubMed Central

Pandalai, Sudha; Wulsin, Victoria; Chun, HeeKyoung

2012-01-01

Most diseases, injuries, and other health conditions experienced by working people are multifactorial, especially as the workforce ages. Evidence supporting the role of work and personal risk factors in the health of working people is frequently underused in developing interventions. Achieving a longer, healthy working life requires a comprehensive preventive approach. To help develop such an approach, we evaluated the influence of both occupational and personal risk factors on workforce health. We present 32 examples illustrating 4 combinatorial models of occupational hazards and personal risk factors (genetics, age, gender, chronic disease, obesity, smoking, alcohol use, prescription drug use). Models that address occupational and personal risk factors and their interactions can improve our understanding of health hazards and guide research and interventions. PMID:22021293

What factors influence time-use of occupational therapists in the workplace? A systematic review.

PubMed

Summers, Bianca E; Laver, Kate E; Nicks, Rebecca J; Lannin, Natasha A

2018-06-01

Health-care expenditure is rapidly increasing in Australia with increasing pressure on health-care services to review processes, improve efficiency and ensure equity in service delivery. The nursing profession have improved efficiency and patient care by investigating time-use to describe current practice and support development of workforce planning models. There is, however, a lack of information to understand factors that impact on occupational therapists time-use in the clinical setting impacting the development of workforce planning models which adapt occupational therapy service delivery to match resources with demand. The objective of this review was to systematically identify known factors which impact on occupational therapists time-use in the clinical setting. A systematic review of Medline, PsycINFO and CINAHL databases and grey literature was completed in September 2016. Two authors independently screened studies for inclusion and quality was evaluated using the Downs and Black scale. Variables impacting on occupational therapists time-use were categorised and thematically analysed to synthesise key themes. Twenty studies met the inclusion criteria and were included in the review. Three key categories of factors influencing time-use were identified. These were: patient-related factors (e.g. level of function, therapy required, type, complexity of injury), therapist-related factors (e.g. experience, clinical vs non-clinical responsibility), and organisational-related factors (e.g. workplace characteristics, availability of staff, presence of students). Occupational therapist time-use in clinical settings is complex and difficult to quantify in research. How occupational therapists spend their time is impacted by a number of patient, clinician and service related factors reflecting the breadth of occupational therapy practice and client-centred nature of the profession. © 2018 Occupational Therapy Australia.

Histone deacetylases in memory and cognition.

PubMed

Penney, Jay; Tsai, Li-Huei

2014-12-09

Over the past 30 years, lysine acetylation of histone and nonhistone proteins has become established as a key modulator of gene expression regulating numerous aspects of cell biology. Neuronal growth and plasticity are no exception; roles for lysine acetylation and deacetylation in brain function and dysfunction continue to be uncovered. Transcriptional programs coupling synaptic activity to changes in gene expression are critical to the plasticity mechanisms underlying higher brain functions. These transcriptional programs can be modulated by changes in histone acetylation, and in many cases, transcription factors and histone-modifying enzymes are recruited together to plasticity-associated genes. Lysine acetylation, catalyzed by lysine acetyltransferases (KATs), generally promotes cognitive performance, whereas the opposing process, catalyzed by histone lysine deacetylases (HDACs), appears to negatively regulate cognition in multiple brain regions. Consistently, mutation or deregulation of different KATs or HDACs contributes to neurological dysfunction and neurodegeneration. HDAC inhibitors have shown promise as a treatment to combat the cognitive decline associated with aging and neurodegenerative disease, as well as to ameliorate the symptoms of depression and posttraumatic stress disorder, among others. In this review, we discuss the evidence for the roles of HDACs in cognitive function as well as in neurological disorders and disease. In particular, we focus on HDAC2, which plays a central role in coupling lysine acetylation to synaptic plasticity and mediates many of the effects of HDAC inhibition in cognition and disease. Copyright © 2014, American Association for the Advancement of Science.

Antidepressant-Like Effects of Acupuncture-Insights From DNA Methylation and Histone Modifications of Brain-Derived Neurotrophic Factor.

PubMed

Jiang, Huili; Zhang, Xuhui; Lu, Jun; Meng, Hong; Sun, Yang; Yang, Xinjing; Zhao, Bingcong; Bao, Tuya

2018-01-01

Sensitive and stable biomarkers that facilitate depression detection and monitor the antidepressant efficiency are currently unavailable. Thus, the objective is to investigate the potential of DNA methylation and histone modifications of brain-derived neurotrophic factor (BDNF) in monitoring severity and antidepressive effects of acupuncture. The depression rat model was imitated by social isolation and chronic unpredicted mild stress (CUMS). The expression of serum BDNF was detected by enzyme-linked immunosorbent assay (ELISA), the hippocampal BDNF, acetylation levels in histone H3 lysine 9 (acH3K9), and HDAC2 by Western blot, the hippocampal mRNA of BDNF by RT-polymerase chain reaction (PCR). The DNA methylation patterns of the promoter I of BDNF was detected by MS-PCR. We investigated that the expression of BDNF in serum and hippocampus were significantly downregulated compared with controls. The same trend was found in mRNA of BDNF. Notably, acupuncture reversed the downregulation of BDNF in serum and hippocampus and mRNA of BDNF compared with model group. Acupuncture reversed the CUMS-induced downregulation of hippocampal acH3K9. On the contrary, the CUMS-induced upregulation of hippocampal HDAC2 in model group was significantly reversed by acupuncture. Collectively, the antidepressant effect of acupuncture might be mediated by regulating the DNA methylation and histone modifications of BDNF, which may represent novel biomaker for detection of depression and monitoring severity and antidepressive effects.

Occupational exposure factors for mental and behavioral disorders at work: The FOREC thesaurus.

PubMed

Chamoux, Alain; Lambert, Céline; Vilmant, Audrey; Lanhers, Charlotte; Agius, Raymond; Boutaleb, Mounir; Bonneterre, Vincent; Naughton, Geraldine; Pereira, Bruno; Djeriri, Khalid; Ben-Brik, Eric; Breton, Christine; De Clavière, Caroline; Letheux, Corinne; Paolillo, Anne-Gaëlle; Valenty, Madeleine; Vandenberghe, Odile; Aeschlimann, Marie-Pierre; Lasfargues, Gérard; Lesage, Francois-Xavier; Dutheil, Frédéric

2018-01-01

Mental disorders in the workplace are a major public health problem. Knowledge of the impact of the psychosocial work environment on mental and behavioral disorders can assist occupational physicians in the identification and description of occupational risk situations, and help to define priority actions. However, no classification for occupational exposure factors is currently available. We aimed to build a thesaurus of "Organizational, Relational, Ethical and other Contributing Factors" (FOREC) linked with the onset of mental and behavioral disorders. The French Agency for Food, Environmental and Occupational Health and Safety (ANSES) initiated and supervised a multidisciplinary working group consisting of the representatives of the main French occupational and public health actors. All decisions were accepted on a consensus basis. This collaborative work led to the classification of occupational exposure factors for mental and behavioral disorders in the workplace. To test this thesaurus in clinical practice, a French multicenter study was implemented. Patients were workers referred to the Occupational Disease Centers for mental health issues at work. Factors contributing to mental and behavioral disorders among workers were identified and coded retrospectively from the worker's point of view using the FOREC thesaurus. We recruited 323 workers, aged 44.9±9.2 years, of which 31.3% were men. The most commonly encountered disorders were generalized anxiety disorders (106 workers, 32.8%) and moderate depressive episodes (86 workers, 26.7%). We identified 1357 factors, i.e. an average of 4.2 factors per worker. Among them, 575 (42.4%) were relational and 515 (37.9%) were organizational. All factors identified during consultations were described in the thesaurus. We built the first thesaurus of "Organizational, Relational, Ethical and other Contributing Factors" (FOREC) that may help to generate profiles of mental and behavioral disorders at work. Encoding and

[Chromosomal proteins: histones and acid proteins].

PubMed

Salvini, M; Gabrielli, F

1976-01-01

Experimental data about the chemistry and the biology of chromosomal proteins are reviewed. Paragraphs include: aminoacid sequential data and post-translational covalent modications of histones, histone chemical differences in different tissues of the same species and in homologous organs of different species, histone synthesis subcellular localization and its association with DNA synthesis, histone synthesis transcriptional and translational control, histone synthesis during meiosis, oogenesis and early embryogenesis. The possible role of histones as controllers of gene expression is discussed and a model of primary structure of chromatine is proposed. The "acidic proteins" data concern the high tissue eterogenity of these proteins and their role in the steroid-hormon-controlled gene expression. The possible role of acidic proteins as general controllers of gene expression in eucariotic cells is discussed.

Aberrant histone deacetylase2-mediated histone modifications and synaptic plasticity in the amygdala predisposes to anxiety and alcoholism.

PubMed

Moonat, Sachin; Sakharkar, Amul J; Zhang, Huaibo; Tang, Lei; Pandey, Subhash C

2013-04-15

Epigenetic mechanisms have been implicated in psychiatric disorders, including alcohol dependence. However, the epigenetic basis and role of specific histone deacetylase (HDAC) isoforms in the genetic predisposition to anxiety and alcoholism is unknown. We measured amygdaloid HDAC activity, levels of HDAC isoforms, and histone H3 acetylation in selectively bred alcohol-preferring (P) and -nonpreferring (NP) rats. We employed HDAC2 small interfering RNA infusion into the central nucleus of amygdala (CeA) of P rats to determine the causal role of HDAC2 in anxiety-like and alcohol-drinking behaviors. Chromatin immunoprecipitation analysis was performed to examine the histone acetylation status of brain-derived neurotrophic factor (Bdnf) and activity-regulated cytoskeleton associated protein (Arc) genes. Golgi-Cox staining was performed to measure dendritic spine density. We found that P rats innately display higher nuclear HDAC activity and HDAC2 but not HDAC 1, 3, 4, 5, and 6 protein levels and lower acetylation of H3-K9 but not H3-K14, in the CeA and medial nucleus of amygdala compared with NP rats. Acute ethanol exposure decreased amygdaloid HDAC activity and HDAC2 protein levels, increased global and gene (Bdnf and Arc)-specific histone acetylation, and attenuated anxiety-like behaviors in P rats but had no effects in NP rats. The HDAC2 knockdown in the CeA attenuated anxiety-like behaviors and voluntary alcohol but not sucrose consumption in P rats and increased histone acetylation of Bdnf and Arc with a resultant increase in protein levels that correlated with increased dendritic spine density. These novel data demonstrate the role of HDAC2-mediated epigenetic mechanisms in anxiety and alcoholism. Published by Elsevier Inc.

Optimized methods of chromatin immunoprecipitation for profiling histone modifications in industrial microalgae Nannochloropsis spp.

PubMed

Wei, Li; Xu, Jian

2018-06-01

Epigenetic factors such as histone modifications play integral roles in plant development and stress response, yet their implications in algae remain poorly understood. In the industrial oleaginous microalgae Nannochloropsis spp., the lack of an efficient methodology for chromatin immunoprecipitation (ChIP), which determines the specific genomic location of various histone modifications, has hindered probing the epigenetic basis of their photosynthetic carbon conversion and storage as oil. Here, a detailed ChIP protocol was developed for Nannochloropsis oceanica, which represents a reliable approach for the analysis of histone modifications, chromatin state, and transcription factor-binding sites at the epigenetic level. Using ChIP-qPCR, genes related to photosynthetic carbon fixation in this microalga were systematically assessed. Furthermore, a ChIP-Seq protocol was established and optimized, which generated a genome-wide profile of histone modification events, using histone mark H3K9Ac as an example. These results are the first step for appreciation of the chromatin landscape in industrial oleaginous microalgae and for epigenetics-based microalgal feedstock development. © 2018 Phycological Society of America.

Factors affecting clinical reasoning of occupational therapists: a qualitative study

PubMed Central

Shafaroodi, Narges; Kamali, Mohammad; Parvizy, Soroor; Mehraban, Afsoon Hassani; O’Toole, Giyn

2014-01-01

Background: Clinical reasoning is generally defined as the numerous modes of thinking that guide clinical practice but little is known about the factors affecting how occupational therapists manage the decision-making process. The aim of this qualitative study was to explore the factors influencing the clinical reasoning of occupational therapists. Methods: Twelve occupational therapy practitioners working in mental and physical dysfunction fields participated in this study. The sampling method was purposeful and interviews were continued until data saturation. All the interviews were recorded and transcribed. The data were analyzed through a qualitative content analysis method. Results: There were three main themes. The first theme: socio-cultural conditions included three subthemes: 1- client beliefs; 2- therapist values and beliefs; 3- social attitude to disability. The second theme: individual attributions included two subthemes 1- client attributions; 2- therapist attributions. The final theme was the workplace environment with the three subthemes: 1- knowledge of the managers of rehabilitation services, 2- working in an inter-professional team; 3- limited clinical facilities and resources. Conclusion: In this study, the influence of the attitudes and beliefs of client, therapist and society about illness, abilities and disabilities upon reasoning was different to previous studies. Understanding these factors, especially the socio-cultural beliefs basis can play a significant role in the quality of occupational therapy services. Accurate understanding of these influential factors requires more extensive qualitative and quantitative studies. PMID:25250253

Gallic Acid Decreases Inflammatory Cytokine Secretion Through Histone Acetyltransferase/Histone Deacetylase Regulation in High Glucose-Induced Human Monocytes.

PubMed

Lee, Wooje; Lee, Sang Yeol; Son, Young-Jin; Yun, Jung-Mi

2015-07-01

Hyperglycemia contributes to diabetes and several diabetes-related complications. Gallic acid is a polyhydroxy phenolic compound found in various natural products. In this study, we investigated the effects and mechanism of gallic acid on proinflammatory cytokine secretion in high glucose-induced human monocytes (THP-1 cells). THP-1 cells were cultured under normoglycemic or hyperglycemic conditions, in the absence or presence of gallic acid. Hyperglycemic conditions significantly induced histone acetylation, nuclear factor-κB (NF-κB) activation, and proinflammatory cytokine release from THP-1 cells, whereas gallic acid suppressed NF-κB activity and cytokine release. It also significantly reduced CREB-binding protein/p300 (CBP/p300, a NF-κB coactivator) gene expression, acetylation levels, and CBP/p300 histone acetyltransferase (HAT) activity. In addition, histone deacetylase 2 (HDAC2) expression was significantly induced. These results suggest that gallic acid inhibits hyperglycemic-induced cytokine production in monocytes through epigenetic changes involving NF-κB. Therefore, gallic acid may have potential for the treatment and prevention of diabetes and its complications.

Dynamic motif occupancy (DynaMO) analysis identifies transcription factors and their binding sites driving dynamic biological processes

PubMed Central

Kuang, Zheng; Ji, Zhicheng

2018-01-01

Abstract Biological processes are usually associated with genome-wide remodeling of transcription driven by transcription factors (TFs). Identifying key TFs and their spatiotemporal binding patterns are indispensable to understanding how dynamic processes are programmed. However, most methods are designed to predict TF binding sites only. We present a computational method, dynamic motif occupancy analysis (DynaMO), to infer important TFs and their spatiotemporal binding activities in dynamic biological processes using chromatin profiling data from multiple biological conditions such as time-course histone modification ChIP-seq data. In the first step, DynaMO predicts TF binding sites with a random forests approach. Next and uniquely, DynaMO infers dynamic TF binding activities at predicted binding sites using their local chromatin profiles from multiple biological conditions. Another landmark of DynaMO is to identify key TFs in a dynamic process using a clustering and enrichment analysis of dynamic TF binding patterns. Application of DynaMO to the yeast ultradian cycle, mouse circadian clock and human neural differentiation exhibits its accuracy and versatility. We anticipate DynaMO will be generally useful for elucidating transcriptional programs in dynamic processes. PMID:29325176

Interactions of Histone Acetyltransferase p300 with the Nuclear Proteins Histone and HMGB1, As Revealed by Single Molecule Atomic Force Spectroscopy.

PubMed

Banerjee, S; Rakshit, T; Sett, S; Mukhopadhyay, R

2015-10-22

One of the important properties of the transcriptional coactivator p300 is histone acetyltransferase (HAT) activity that enables p300 to influence chromatin action via histone modulation. p300 can exert its HAT action upon the other nuclear proteins too--one notable example being the transcription-factor-like protein HMGB1, which functions also as a cytokine, and whose accumulation in the cytoplasm, as a response to tissue damage, is triggered by its acetylation. Hitherto, no information on the structure and stability of the complexes between full-length p300 (p300FL) (300 kDa) and the histone/HMGB1 proteins are available, probably due to the presence of unstructured regions within p300FL that makes it difficult to be crystallized. Herein, we have adopted the high-resolution atomic force microscopy (AFM) approach, which allows molecularly resolved three-dimensional contour mapping of a protein molecule of any size and structure. From the off-rate and activation barrier values, obtained using single molecule dynamic force spectroscopy, the biochemical proposition of preferential binding of p300FL to histone H3, compared to the octameric histone, can be validated. Importantly, from the energy landscape of the dissociation events, a model for the p300-histone and the p300-HMGB1 dynamic complexes that HAT forms, can be proposed. The lower unbinding forces of the complexes observed in acetylating conditions, compared to those observed in non-acetylating conditions, indicate that upon acetylation, p300 tends to weakly associate, probably as an outcome of charge alterations on the histone/HMGB1 surface and/or acetylation-induced conformational changes. To our knowledge, for the first time, a single molecule level treatment of the interactions of HAT, where the full-length protein is considered, is being reported.

An integrative review of social and occupational factors influencing health and wellbeing

PubMed Central

Gallagher, MaryBeth; Muldoon, Orla T.; Pettigrew, Judith

2015-01-01

Therapeutic approaches to health and wellbeing have traditionally assumed that meaningful activity or occupation contributes to health and quality of life. Within social psychology, everyday activities and practices that fill our lives are believed to be shaped by structural and systemic factors and in turn these practices can form the basis of social identities. In occupational therapy these everyday activities are called occupations. Occupations can be understood as a contextually bound synthesis of meaningful doing, being, belonging and becoming that influence health and wellbeing. We contend that an integrative review of occupational therapy and social psychology literature will enhance our ability to understand the relationship between social structures, identity and dimensions of occupation by elucidating how they inform one another, and how taken together they augment our understanding of health and wellbeing This review incorporates theoretical and empirical works purposively sampled from databases within EBSCO including CINAHL, psychINFO, psychArticles, and Web of Science. Search terms included: occupation, therapy, social psychology, occupational science, health, wellbeing, identity, structures and combinations of these terms. In presenting this review, we argue that doing, being and belonging may act as an important link to widely acknowledged relationships between social factors and health and wellbeing, and that interventions targeting individual change may be problematic. PMID:26388800

Towards Breaking the Histone Code – Bayesian Graphical Models for Histone Modifications

PubMed Central

Mitra, Riten; Müller, Peter; Liang, Shoudan; Xu, Yanxun; Ji, Yuan

2013-01-01

Background Histones are proteins that wrap DNA around in small spherical structures called nucleosomes. Histone modifications (HMs) refer to the post-translational modifications to the histone tails. At a particular genomic locus, each of these HMs can either be present or absent, and the combinatory patterns of the presence or absence of multiple HMs, or the ‘histone codes,’ are believed to co-regulate important biological processes. We aim to use raw data on HM markers at different genomic loci to (1) decode the complex biological network of HMs in a single region and (2) demonstrate how the HM networks differ in different regulatory regions. We suggest that these differences in network attributes form a significant link between histones and genomic functions. Methods and Results We develop a powerful graphical model under Bayesian paradigm. Posterior inference is fully probabilistic, allowing us to compute the probabilities of distinct dependence patterns of the HMs using graphs. Furthermore, our model-based framework allows for easy but important extensions for inference on differential networks under various conditions, such as the different annotations of the genomic locations (e.g., promoters versus insulators). We applied these models to ChIP-Seq data based on CD4+ T lymphocytes. The results confirmed many existing findings and provided a unified tool to generate various promising hypotheses. Differential network analyses revealed new insights on co-regulation of HMs of transcriptional activities in different genomic regions. Conclusions The use of Bayesian graphical models and borrowing strength across different conditions provide high power to infer histone networks and their differences. PMID:23748248

Factors influencing the occupational trajectory of patients with systemic sclerosis: a qualitative study.

PubMed

Decuman, Saskia; Smith, Vanessa; Grypdonck, Maria; De Keyser, Filip; Verhaeghe, Sofie

2015-01-01

To describe, from the patient's point of view, the factors influencing the occupational trajectory of patients with systemic sclerosis (SSc). This was a qualitative study designed using grounded theory with constant comparison. Data were collected through semi-structured interviews with 14 patients who fulfilled the American College of Rheumatology or Leroy-Medsger criteria for SSc. Based on our interviews, we found that the occupational trajectory of patients with SSc is influenced by the continuous interplay between four groups of factors. The first group concerns the values patients attribute to work, including identity, normality, financial value, social contact, and structure. The meaning of these values and how they relate to each other underlies the desire to work. A second group of factors is those influencing the balance between daily life, work participation, and medical condition (e.g. job content, flexibility in organising work, and the willingness to ask for accommodations at work). The occupational trajectory is also influenced by external factors, including availability of support, know-ledge of the disease, pressure to work, contact with medical professionals, and existing regulations and the patient's knowledge about them. Finally, the occupational trajectory is influenced by personal factors, including socio-demographics, psychological assets, and disease- and work-related personal factors. The decisions patients with SSc take concerning work depend on an interplay between many factors and, especially, on the patients' personal interpretation of these factors. These need to be taken into account when helping patients with SSc determine their occupational trajectory.

Occupational and environmental risk factors of adult primary brain cancers: a systematic review.

PubMed

Gomes, J; Al Zayadi, A; Guzman, A

2011-04-01

The incidence of brain neoplasm has been progressively increasing in recent years in the industrialized countries. One of the reasons for this increased incidence could be better access to health care and improved diagnosis in the industrialized countries. It also appears that Caucasians have a higher incidence than blacks or Hispanics or Asians. A number of risk factors have been identified and described including the genetic, ethnic and age-based factors. Certain occupational and environmental factors are also believed to influence the risk of primary adult brain tumors. Potential occupational and environmental factors include exposure to diagnostic and therapeutic radiations, electromagnetic radiation from cellular phones and other wireless devices, infectious agents, air pollution and residence near landfills and high-voltage power lines and jobs as firefighters, farmers, physician, chemists and jobs in industries such as petrochemical, power generation, synthetic rubber manufacturing, agricultural chemicals manufacturing. The purpose of this systematic review is to examine occupational and environmental risk factors of brain neoplasm. A range of occupational and environmental exposures are evaluated for significance of their relationship with adult primary brain tumors. On the basis of this review we suggest a concurrent evaluation of multiple risk factors both within and beyond occupational and environmental domains. The concurrent approach needs to consider better exposure assessment techniques, lifetime occupational exposures, genotypic and phenotypic characteristics and lifestyle and dietary habits. This approach needs to be interdisciplinary with contributions from neurologists, oncologists, epidemiologists and molecular biologists. Conclusive evidence that has eluded multitude of studies with single focus and single exposure needs to multifaceted and multidisciplinary.

Occupational stress and its related factors among university teachers in China.

PubMed

Sun, Wei; Wu, Hui; Wang, Lie

2011-01-01

University teachers in China are expected to suffer serious occupational stress due to the expanding enrollment in universities without a proportional increase in teacher resources and the fact that all promotions for university teachers are determined based on not only teaching but also the outcome of scientific research. This study was designed to assess the occupational stress among university teachers in China and clarify its risk factors. A cross-sectional study was performed in Liaoning Province, the centralized area of higher education in Northeast China. Eight universities (2 multidiscipline and 6 specialized) and 10% of academic staff each were randomly sampled. Questionnaires pertaining to occupational stress indicated by the Chinese Version Personal Strain Questionnaire (PSQ) and demographic characteristics, health status, work situations, and personal and social resources were distributed in October 2008. A total of 827 effective respondents (response rate 76.4%) became our participants. The average raw score of PSQ was 91.0 among the university teachers. General linear model analysis showed that the factors significantly associated with the PSQ score were, in standardized estimate (β) sequence, mental health, role overload, role insufficiency, social support, monthly income, role limitations due to physical problems, research finance and self-rated disease with adjustment for age and sex. We concluded that, in comparison to work-related factors and social support, mental health is a prominent risk factor for occupational stress in university teachers in China. Improvement of mental health and organizational climate should be considered to lessen the occupational stress of university teachers.

[Mental health status in railway female workers and its occupational influencing factors].

PubMed

Ji, F L; Liu, Z M; Liu, Z S; Zou, J F; Yu, W L; Li, H M; Li, J; Kong, L M; Jiang, Q

2018-02-20

Objective: To investigate the mental health status of railway female workers and related influencing factors, and to provide a scientific strategy for labor protection regulations in railway female workers. Methods: Cluster sampling was used to select 5033 female workers from Jinan, Nanning, Qinghai-Tibet, and Wuhan railway systems in China from January to August, 2016. A uniform reproductive health questionnaire, as well as the Symptom Checklist-90 (SCL-90) , was used to investigate their general information (age, marital status, education level, and family income) , work type (day shift, night shift, or work on shift) , work position, and the presence or absence of exposure to occupational hazardous factors. The score on each factor of SCL-90 and the positive rate of mental health status were calculated. Results: The positive rate of mental health status was 10.6% in railway female workers. The workers exposed to occupational hazardous factors had a significantly higher positive rate of mental health status than those not exposed to occupational hazardous factors (14.20% vs 8.02%, P <0.01) . There were significant differences in the positive rate of mental health status between workers with different ages, marital status, education levels, histories of abortion, or annual family income levels ( P <0.01) . The scores of somatization (1.54±0.62) and horror (1.28±0.47) in SCL-90 were significantly higher than the Chinese adult norm ( P <0.01) . The multivariate logistic regression analysis showed that exposure to occupational hazardous factors, night shift, overwork, and carrying heavy objects were associated with mental health problems ( OR =1.797, 95% CI : 1.393-2.318; OR =0.641, 95% CI : 0.498-0.827; OR =0.586, 95% CI : 0.439-0.783; OR =0.580, 95% CI : 0.378-0.890) . Conclusion: Railway female workers have lower levels of mental health than the general population and are under significant occupational stress. Exposure to occupational hazardous factors, night

Relationship between occupational stress and cardiovascular diseases risk factors in drivers.

PubMed

Biglari, Hamed; Ebrahimi, Mohammad Hossein; Salehi, Maryam; Poursadeghiyan, Mohsen; Ahmadnezhad, Iman; Abbasi, Milad

2016-11-18

Of all work stressors, occupational stress is the leading cause of many disorders among workers. Drivers are classified as a high risk group for work related stress. This study set out to determine the relationship between risk factors of cardiovascular diseases and occupational stress among drivers. Two hundred and twenty two Ilam's intercity drivers were selected for the study. For measuring work stress, the Osipow work stress questionnaire was used. After a 10-h fasting period, systolic and diastolic blood pressure was recorded. Intravenous blood samples were taken to determine cholesterol, triglyceride and blood glucose levels. The independent samples t-test and Pearson's correlation test were used to assess the relationship between variables and occupational stress. Seventy-one percent of the intercity drivers suffered from average to acute stress, and 3.1% of them suffered from acute stress. There was no significant relationship between occupational stress and diastolic blood pressure (p = 0.254) among the drivers. Nevertheless, the Pearson's correlation test demonstrated a strong relationship between work stress and blood glucose (p < 0.01), while no strong correlation was found for blood triglycerides and cholesterol levels. Based on the results, high rates of occupational stress were observed in the Ilam's intercity drivers. Occupational stress may have effect on blood glucose levels but the results did not suggest a considerable relationship between risk factors of cardiovascular diseases and occupational stress among intercity drivers. Int J Occup Med Environ Health 2016;29(6):895-901. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

[Analysis of occupational burnout and its influencing factors of colliery migrant workers in Guizhou Province].

PubMed

Zhao, Xiaodeng; Tuo, Anxie; Peng, Anhui; He, Wanjing; Zhu, Peijia; Yan, Zheng

2015-11-01

To understand the status of occupational burnout of colliery migrant workers and its influencing factors. The occupational burnout of 1161 colliery migrant workers in Jinsha County, Guizhou Province was measured with MBI-GS and the self-made questionnaire. All dimensions of MBI-GS Cronbach's α coefficient was in the range of 0.86-0.88, all 15 items of MBI-GS were subjected to factor analysis, and three latent factors were identified, which explained 68.86% of the total variance and consisted with the theory model. The score of occupational burnout of each dimension, differences in different individual characteristics (physical examination, sleep, et al) were statistically significant (P <0.05). The influence factors of occupational burnout of colliery migrant workers were physical examination, chronic disease, smoking, physical exercise, sleep, initial work in coal mine, production post and labor intensity. MBI-GS can be used to study the occupational burnout of colliery migrant workers. Different individual characteristics effect the occurrence of occupational burnout.

Empirical research on the influencing factors of the occupational stress for construction workers

NASA Astrophysics Data System (ADS)

LV, Xing; WU, Xiang; CI, Huipeng; LIU, Qing; YAO, Yongzheng

2017-04-01

Employee’s occupational stress and safety performance are highly related, which has been generally recognized by the researchers. We did this research to understand the status of the stress for construction workers, and explore the influence factors of pressure source with characteristics of construction industry. Based on the results of previous studies, we designed questionnaire to collect the influence factors on occupational stressors. The study selected workers from certain construction units at the grass-roots level as sample source. According to the results of the questionnaire, we redesigned the interview outline, and did the semi-structured interviews on workers randomly selected. Finally, we developed a scale which combined the characteristics of construction projects in China. Using SPSS software for factor analysis, reliability analysis, and descriptive statistical analysis, the results show that there are six factors affecting the workers’ occupational stress, including The Work Itself, Family-Work, Career Development, Organization Style, Interpersonal Relationship and Role Management Style. The work itself is the main sources of occupational stress. The results can be used by the construction company to provide guidance for workers to control and manage occupational stress.

Histone modification: cause or cog?

PubMed

Henikoff, Steven; Shilatifard, Ali

2011-10-01

Histone modifications are key components of chromatin packaging but whether they constitute a 'code' has been contested. We believe that the central issue is causality: are histone modifications responsible for differences between chromatin states, or are differences in modifications mostly consequences of dynamic processes, such as transcription and nucleosome remodeling? We find that inferences of causality are often based on correlation and that patterns of some key histone modifications are more easily explained as consequences of nucleosome disruption in the presence of histone modifying enzymes. We suggest that the 35-year-old DNA accessibility paradigm provides a mechanistically sound basis for understanding the role of nucleosomes in gene regulation and epigenetic inheritance. Based on this view, histone modifications and variants contribute to diversification of a chromatin landscape shaped by dynamic processes that are driven primarily by transcription and nucleosome remodeling. Copyright © 2011 Elsevier Ltd. All rights reserved.

Modulation of the functional association between the HIV-1 intasome and the nucleosome by histone amino-terminal tails.

PubMed

Benleulmi, Mohamed S; Matysiak, Julien; Robert, Xavier; Miskey, Csaba; Mauro, Eric; Lapaillerie, Delphine; Lesbats, Paul; Chaignepain, Stéphane; Henriquez, Daniel R; Calmels, Christina; Oladosu, Oyindamola; Thierry, Eloïse; Leon, Oscar; Lavigne, Marc; Andreola, Marie-Line; Delelis, Olivier; Ivics, Zoltán; Ruff, Marc; Gouet, Patrice; Parissi, Vincent

2017-11-28

Stable insertion of the retroviral DNA genome into host chromatin requires the functional association between the intasome (integrase·viral DNA complex) and the nucleosome. The data from the literature suggest that direct protein-protein contacts between integrase and histones may be involved in anchoring the intasome to the nucleosome. Since histone tails are candidates for interactions with the incoming intasomes we have investigated whether they could participate in modulating the nucleosomal integration process. We show here that histone tails are required for an optimal association between HIV-1 integrase (IN) and the nucleosome for efficient integration. We also demonstrate direct interactions between IN and the amino-terminal tail of human histone H4 in vitro. Structure/function studies enabled us to identify amino acids in the carboxy-terminal domain of IN that are important for this interaction. Analysis of the nucleosome-binding properties of catalytically active mutated INs confirmed that their ability to engage the nucleosome for integration in vitro was affected. Pseudovirus particles bearing mutations that affect the IN/H4 association also showed impaired replication capacity due to altered integration and re-targeting of their insertion sites toward dynamic regions of the chromatin with lower nucleosome occupancy. Collectively, our data support a functional association between HIV-1 IN and histone tails that promotes anchoring of the intasome to nucleosomes and optimal integration into chromatin.

Histone H4 acetylation regulates behavioral inter-individual variability in zebrafish.

PubMed

Román, Angel-Carlos; Vicente-Page, Julián; Pérez-Escudero, Alfonso; Carvajal-González, Jose M; Fernández-Salguero, Pedro M; de Polavieja, Gonzalo G

2018-04-25

Animals can show very different behaviors even in isogenic populations, but the underlying mechanisms to generate this variability remain elusive. We use the zebrafish (Danio rerio) as a model to test the influence of histone modifications on behavior. We find that laboratory and isogenic zebrafish larvae show consistent individual behaviors when swimming freely in identical wells or in reaction to stimuli. This behavioral inter-individual variability is reduced when we impair the histone deacetylation pathway. Individuals with high levels of histone H4 acetylation, and specifically H4K12, behave similarly to the average of the population, but those with low levels deviate from it. More precisely, we find a set of genomic regions whose histone H4 acetylation is reduced with the distance between the individual and the average population behavior. We find evidence that this modulation depends on a complex of Yin-yang 1 (YY1) and histone deacetylase 1 (HDAC1) that binds to and deacetylates these regions. These changes are not only maintained at the transcriptional level but also amplified, as most target regions are located near genes encoding transcription factors. We suggest that stochasticity in the histone deacetylation pathway participates in the generation of genetic-independent behavioral inter-individual variability.

Factors influencing occupancy of nest cavities in recently burned forests

Treesearch

Victoria A. Saab; Jonathan Dudley; William L. Thompson

2004-01-01

Recently burned forests in western North America provide nesting habitat for many species of cavity-nesting birds. However, little is understood about the time frame and the variables affecting occupancy of postfire habitats by these birds. We studied factors influencing the occupancy and reuse of nest cavities from 1–7 years after fire in two burned sites of western...

A multifaceted role for MOF histone modifying factor in genome maintenance

PubMed Central

Mujoo, Kalpana; Hunt, Clayton R.; Horikoshi, Nobuo; Pandita, Tej K.

2016-01-01

MOF (males absent on the first) was initially identified as a dosage compensation factor in Drosophila that acetylates lysine 16 of histone H4 (H4K16ac) and increased gene transcription from the single copy male X-chromosome. In humans, however, the ortholog of Drosophila MOF has been shown to interact with a range of proteins that extend its potential significance well beyond transcription. For example, recent results indicate MOF is an upstream regulator of the ATM (ataxia-telangiectasia mutated) protein, the loss of which is responsible for ataxia telangiectasia (AT). ATM is a key regulatory kinase that interacts with and phosphorylates multiple substrates that influence critical, cell-cycle control and DNA damage repair pathways in addition to other pathways. Thus, directly or indirectly, MOF may be involved in a wide range of cellular functions. This review will focus on the contribution of MOF to cellular DNA repair and new results that are beginning to examine the in vivo physiological role of MOF. PMID:27038808

The histone acetyltransferase p300 inhibitor C646 reduces pro-inflammatory gene expression and inhibits histone deacetylases

PubMed Central

van den Bosch, Thea; Boichenko, Alexander; Leus, Niek G. J.; Eleni Ourailidou, Maria; Wapenaar, Hannah; Rotili, Dante; Mai, Antonello; Imhof, Axel; Bischoff, Rainer; Haisma, Hidde J.; Dekker, Frank J.

2016-01-01

Lysine acetylations are reversible posttranslational modifications of histone and non-histone proteins that play important regulatory roles in signal transduction cascades and gene expression. Lysine acetylations are regulated by histone acetyltransferases as writers and histone deacetylases as erasers. Because of their role in signal transduction cascades, these enzymes are important players in inflammation. Therefore, applications of histone acetyltransferase inhibitors to reduce inflammatory responses are interesting. Among the few histone acetyltransferase inhibitors described, C646 is one of the most potent (Ki of 0.4 μM for histone acetyltransferase p300). C646 was described to regulate the NF-κB pathway; an important pathway in inflammatory responses, which is regulated by acetylation. Interestingly, this pathway has been implicated in asthma and COPD. Therefore we hypothesized that via regulation of the NF-κB signaling pathway, C646 can inhibit pro-inflammatory gene expression, and have potential for the treatment of inflammatory lung diseases. In line with this, here we demonstrate that C646 reduces pro-inflammatory gene expression in RAW264.7 murine macrophages and murine precision-cut lung slices. To unravel its effects on cellular substrates we applied mass spectrometry and found, counterintuitively, a slight increase in acetylation of histone H3. Based on this finding, and structural features of C646, we presumed inhibitory activity of C646 on histone deacetylases, and indeed found inhibition of histone deacetylases from 7 μM and higher concentrations. This indicates that C646 has potential for further development towards applications in the treatment of inflammation, however, its newly discovered lack of selectivity at higher concentrations needs to be taken into account. PMID:26718586

[Occupational factors influencing lung cancer in women in epidemiological studies].

PubMed

Swiatkowska, Beata

2011-01-01

Lung cancer is the most common cancer in men, although the alarming statistics of recent years indicate that this pathology affects also more likely a group of women and in recent years has become the leading cause of cancer deaths among Polish women. This article presents the main issues relating to occupational determinants of lung cancer in women. The results of the analysis show that the number of neoplastic diseases, including the lung cancer, recognized as an occupational disease in Poland is low, particularly among women. A major factor hampering the certification of occupational etiology of lung cancer is a long latency period, no differences in terms of the clinical and morphological characteristics from lung cancer occurring in the general population, and relatively small number of identified occupational carcinogens. Analysis of the available literature on the adverse workplace conditions shows that only a few epidemiological studies focus on the problem of job-related risk among women, and only some of them provide detailed results for lung cancer. Moreover, the abundant literature on the subject concerning the male workers might not be fully relevant because of possible differences in hormonal, genetic and other gender-related biological differences that may significantly modify the risk of cancer in women. These aspects cause that the true contribution of occupational factors to the risk of lung cancer, particularly in women, is underestimated.

Nitric Oxide Modulates Histone Acetylation at Stress Genes by Inhibition of Histone Deacetylases1[OPEN

PubMed Central

Mengel, Alexander; Ageeva, Alexandra; Durner, Jörg

2017-01-01

Histone acetylation, which is an important mechanism to regulate gene expression, is controlled by the opposing action of histone acetyltransferases and histone deacetylases (HDACs). In animals, several HDACs are subjected to regulation by nitric oxide (NO); in plants, however, it is unknown whether NO affects histone acetylation. We found that treatment with the physiological NO donor S-nitrosoglutathione (GSNO) increased the abundance of several histone acetylation marks in Arabidopsis (Arabidopsis thaliana), which was strongly diminished in the presence of the NO scavenger 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. This increase was likely triggered by NO-dependent inhibition of HDAC activity, since GSNO and S-nitroso-N-acetyl-dl-penicillamine significantly and reversibly reduced total HDAC activity in vitro (in nuclear extracts) and in vivo (in protoplasts). Next, genome-wide H3K9/14ac profiles in Arabidopsis seedlings were generated by chromatin immunoprecipitation sequencing, and changes induced by GSNO, GSNO/2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide or trichostatin A (an HDAC inhibitor) were quantified, thereby identifying genes that display putative NO-regulated histone acetylation. Functional classification of these genes revealed that many of them are involved in the plant defense response and the abiotic stress response. Furthermore, salicylic acid, which is the major plant defense hormone against biotrophic pathogens, inhibited HDAC activity and increased histone acetylation by inducing endogenous NO production. These data suggest that NO affects histone acetylation by targeting and inhibiting HDAC complexes, resulting in the hyperacetylation of specific genes. This mechanism might operate in the plant stress response by facilitating the stress-induced transcription of genes. PMID:27980017

Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of Parkinson’s is associated with histone acetylation and up-regulation of neurotrophic factors

PubMed Central

Harrison, Ian F; Crum, William R; Vernon, Anthony C; Dexter, David T

2015-01-01

Background and Purpose Histone hypoacetylation is associated with Parkinson's disease (PD), due possibly to an imbalance in the activities of enzymes responsible for histone (de)acetylation; correction of which may be neuroprotective/neurorestorative. This hypothesis was tested using the anti-epileptic drug sodium valproate, a known histone deacetylase inhibitor (HDACI), utilizing a delayed-start study design in the lactacystin rat model of PD. Experimental Approach The irreversible proteasome inhibitor lactacystin was unilaterally injected into the substantia nigra of Sprague–Dawley rats that subsequently received valproate for 28 days starting 7 days after lactacystin lesioning. Longitudinal motor behavioural testing, structural MRI and post-mortem assessment of nigrostriatal integrity were used to track changes in this model of PD and quantify neuroprotection/restoration. Subsequent cellular and molecular analyses were performed to elucidate the mechanisms underlying valproate's effects. Key Results Despite producing a distinct pattern of structural re-modelling in the healthy and lactacystin-lesioned brain, delayed-start valproate administration induced dose-dependent neuroprotection/restoration against lactacystin neurotoxicity, characterized by motor deficit alleviation, attenuation of morphological brain changes and restoration of dopaminergic neurons in the substantia nigra. Molecular analyses revealed that valproate alleviated lactacystin-induced histone hypoacetylation and induced up-regulation of brain neurotrophic/neuroprotective factors. Conclusions and Implications The histone acetylation and up-regulation of neurotrophic/neuroprotective factors associated with valproate treatment culminate in a neuroprotective and neurorestorative phenotype in this animal model of PD. As valproate induced structural re-modelling of the brain, further research is required to determine whether valproate represents a viable candidate for disease treatment; however

Total chemical synthesis of modified histones

NASA Astrophysics Data System (ADS)

Qi, Yun-Kun; Ai, Hua-Song; Li, Yi-Ming; Yan, Baihui

2018-02-01

In the post-genome era, epigenetics has received increasing attentions in recent years. The post-translational modifications (PTMs) of four core histones play central roles in epigenetic regulation of eukaryotic genome by either directly altering the biophysical properties of nucleosomes or by recruiting other effector proteins. In order to study the biological functions and structural mechanisms of these histone PTMs, an obligatory step is to prepare a sufficient amount of homogeneously modified histones. This task cannot be fully accomplished either by recombinant technology or enzymatic modification. In this context, synthetic chemists have developed novel protein synthetic tools and state-of-the-art chemical ligation strategies for the preparation of homologous modified histones. In this review, we summarize the recent advances in the preparation of modified histones, focusing on the total chemical synthesis strategies. The importance and potential of synthetic chemistry for the study of histone code will be also discussed.

Histones: Controlling Tumor Signaling Circuitry

PubMed Central

Martins, Manoela D.; Castilho, Rogerio M.

2014-01-01

Epigenetic modifications constitute the next frontier in tumor biology research. Post-translation modification of histones dynamically influences gene expression independent of alterations to the DNA sequence. These mechanisms are often mediated by histone linkers or by proteins associated with the recruitment of DNA-binding proteins, HDAC I and II interacting proteins and transcriptional activators, coactivators or corepressors. Early evidence suggested that histones and their modifiers are involved in sophisticated processes that modulate tumor behavior and cellular phenotype. In this review, we discuss how recent discoveries about chromatin modifications, particularly histone acetylation, are shaping our knowledge of cell biology and our understanding of the molecular circuitry governing tumor progression and consider whether recent insights may extend to novel therapeutic approaches. Furthermore, we discuss the latest oncogenomic findings in Head and Neck Squamous Cell Carcinoma (HNSCC) from studies using Next Generation Sequencing (NGS) technology and highlight the impact of mutations identified in histones and their modifiers. PMID:25177526

The role of occupational activities and work environment in occupational injury and interplay of personal factors in various age groups among Indian and French coalminers.

PubMed

Bhattacherjee, Ashis; Kunar, Bijay Mihir; Baumann, Michele; Chau, Nearkasen

2013-12-01

The role of occupational hazards in occupational injury may be mediated by individual factors across various age groups. This study assessed the role of occupational hazards as well as contribution of individual factors to injuries among Indian and French coalminers. We conducted a case-control study on 245 injured workers and on 330 controls without any injuries from Indian coal mines using face-to-face interviews, and a retrospective study on 516 French coalminers using a self-administered questionnaire including potential occupational and personal factors. Data were analyzed using logistic models. The annual rate of injuries was 5.5% for Indian coalminers and 14.9% for the French ones. Logistic model including all occupational factors showed that major injury causes were: hand-tools, material handling, machines, and environment/work-geological/strata conditions among Indian miners (adjusted odds-ratios 2.01 to 3.30) and biomechanical exposure score among French miners (adjusted odds-ratio 3.01 for score the 1-4, 3.47 for the score 5-7, and 7.26 for score ≥ 8, vs. score 0). Personal factors among Indian and French coalminers reduced/exacerbated the roles of various occupational hazards to a different extent depending on workers' age. We conclude that injury roles of occupational hazards were reduced or exacerbated by personal factors depending on workers' age in both populations. This knowledge is useful when designing prevention which should definitely consider workers' age.

Zac1 is a histone acetylation-regulated NF-κB suppressor that mediates histone deacetylase inhibitor-induced apoptosis.

PubMed

Shu, G; Tang, Y; Zhou, Y; Wang, C; Song, J-G

2011-12-01

Histone deacetylase (HDAC) inhibitors are a class of promising anticancer reagents. They are able to induce apoptosis in embryonic carcinoma (EC) cells. However, the underlying mechanism remains poorly understood. Here we show that increased expression of zinc-finger protein regulator of apoptosis and cell-cycle arrest (Zac1) is implicated in HDAC inhibitor-induced apoptosis in F9 and P19 EC cells. By chromatin immunoprecipitation analysis we identified that increased Zac1 expression is mediated by histone acetylation of the Zac1 promoter region. Knockdown of Zac1 inhibited HDAC inhibitor-induced cell apoptosis. Moreover, HDAC inhibitors repressed nuclear factor-κB (NF-κB) activity, and this effect is abrogated by Zac1 knockdown. Consistently, Zac1 overexpression suppressed cellular NF-κB activity. Further investigation showed that Zac1 inhibits NF-κB activity by interacting with the C-terminus of the p65 subunit, which suppresses the phosphorylation of p65 at Ser468 and Ser536 residues. These results indicate that Zac1 is a histone acetylation-regulated suppressor of NF-κB, which is induced and implicated in HDAC inhibitor-mediated EC cell apoptosis.

A Common Histone Modification Code on C4 Genes in Maize and Its Conservation in Sorghum and Setaria italica1[W][OA

PubMed Central

Heimann, Louisa; Horst, Ina; Perduns, Renke; Dreesen, Björn; Offermann, Sascha; Peterhansel, Christoph

2013-01-01

C4 photosynthesis evolved more than 60 times independently in different plant lineages. Each time, multiple genes were recruited into C4 metabolism. The corresponding promoters acquired new regulatory features such as high expression, light induction, or cell type-specific expression in mesophyll or bundle sheath cells. We have previously shown that histone modifications contribute to the regulation of the model C4 phosphoenolpyruvate carboxylase (C4-Pepc) promoter in maize (Zea mays). We here tested the light- and cell type-specific responses of three selected histone acetylations and two histone methylations on five additional C4 genes (C4-Ca, C4-Ppdk, C4-Me, C4-Pepck, and C4-RbcS2) in maize. Histone acetylation and nucleosome occupancy assays indicated extended promoter regions with regulatory upstream regions more than 1,000 bp from the transcription initiation site for most of these genes. Despite any detectable homology of the promoters on the primary sequence level, histone modification patterns were highly coregulated. Specifically, H3K9ac was regulated by illumination, whereas H3K4me3 was regulated in a cell type-specific manner. We further compared histone modifications on the C4-Pepc and C4-Me genes from maize and the homologous genes from sorghum (Sorghum bicolor) and Setaria italica. Whereas sorghum and maize share a common C4 origin, C4 metabolism evolved independently in S. italica. The distribution of histone modifications over the promoters differed between the species, but differential regulation of light-induced histone acetylation and cell type-specific histone methylation were evident in all three species. We propose that a preexisting histone code was recruited into C4 promoter control during the evolution of C4 metabolism. PMID:23564230

Occupational stress and cardiovascular risk factors in high-ranking government officials and office workers.

PubMed

Mirmohammadi, Seyyed Jalil; Taheri, Mahmoud; Mehrparvar, Amir Houshang; Heydari, Mohammad; Saadati Kanafi, Ali; Mostaghaci, Mehrdad

2014-08-01

Cardiovascular diseases are among the most important sources of mortality and morbidity, and have a high disease burden. There are some major well-known risk factors, which contribute to the development of these diseases. Occupational stress is caused due to imbalance between job demands and individual's ability, and it has been implicated as an etiology for cardiovascular diseases. This study was conducted to evaluate the cardiovascular risk factors and different dimensions of occupational stress in high-ranking government officials, comparing an age and sex-matched group of office workers with them. We invited 90 high-ranking officials who managed the main governmental offices in a city, and 90 age and sex-matched office workers. The subjects were required to fill the occupational role questionnaire (Osipow) which evaluated their personal and medical history as well as occupational stress. Then, we performed physical examination and laboratory tests to check for cardiovascular risk factors. Finally, the frequency of cardiovascular risk factors and occupational stress of two groups were compared. High-ranking officials in our study had less work experience in their current jobs and smoked fewer pack-years of cigarette, but they had higher waist and hip circumference, higher triglyceride level, more stress from role overload and responsibility, and higher total stress score. Our group of office workers had more occupational stress because of role ambiguity and insufficiency, but their overall job stress was less than officials. The officials have higher scores in some dimensions of occupational stress and higher overall stress score. Some cardiovascular risk factors were also more frequent in managers.

[Etiological factors of carpal tunnel syndrome in subjects occupationally exposed to monotype wrist movements].

PubMed

Lewańska, Magdalena; Walusiak-Skorupa, Jolanta

2014-01-01

Carpal tunnel syndrome (CTS) is the most common neuropathy of upper limbs and a leading cause of upper extremity musculoskeletal disorders, in terms of work exposure, repetitive and forceful exertions of the hand and use of vibrating hand tools. The aim of the study was to evaluate etiological factors of carpal tunnel syndrome in subjects occupationally exposed to monotype movements in wrist. We conducted the retrospective analysis of 300 patients (261 women, 39 men), mean age 52 years (standard deviation: +/-6.93) hospitalized with the suspicion of occupational CTS. The study revealed high percentage (68.7%) of diseases and systemic factors involved in the pathogenesis of CTS in the analyzed population, especially obesity (32%), thyroid diseases (28.7%), hormone replacement therapy and/or oophorectomy (16.3%) and diabetes mellitus (12%). In 111 patients the coexistence of at least a couple of potential etiological factors of the neuropathy was recognized. Clinical analysis and occupational exposure allowed to diagnose occupational carpal tunnel syndrome in 18 (6%) patients only. The undeniable long-term (20(.2+/-9.3 years) occupational exposure to repetitive, forceful movements in the wrist was observed in this group. The results of our study indicated that non-occupational etiological factors of CTS predominated and in 37% of patients at least several factors were found. The analysis showed the high prevalence of CTS in workers employed in various sectors of industry, including so called "blue collar" workers. Our study confirmed the multifactorial etiology of carpal tunnel syndrome, however, occupational agents contributed to only 6% of cases.

Incidence Patterns and Occupational Risk Factors of Human Brucellosis in Greece, 2004-2015.

PubMed

Lytras, T; Danis, K; Dounias, G

2016-10-01

Brucellosis is the most common bacterial zoonosis worldwide. Greece has the highest reported incidence among EU countries. However, occupational risk factors have not been well described. To determine the incidence patterns and exposure risk factors of brucellosis in Greece. We used national-level surveillance and occupational denominator data to estimate the incidence patterns and exposure risk factors of brucellosis in Greece, with particular emphasis on occupation. Between November 2003 and December 2015 a total of 2159 human brucellosis cases was reported. The mean incidence rate was 1.62 per 100 000 population per year. A large majority of cases (77.1%) reported consumption of unpasteurized milk or contact with livestock animals. Most cases occured in farmers and livestock breeders (1079 [87.7%] of 1231 cases reporting their occupation), corresponding to an annual incidence of 7.1 per 100 000. However, there were other occupations with a similar or higher risk: butchers and abattoir workers (12.7 per 100 000), laboratory personnel (3.1 per 100 000), while the highest risk was for veterinarians (53.2 per 100 000). Brucellosis incidence in specific occupational groups was much higher than in the general population. These results underline the importance of collecting information on occupation, both during the diagnostic process and in the surveillance system. Besides efforts to control brucellosis in animals, organized prevention efforts are needed within an occupational health framework, especially for the most vulnerable workers.

Using a model comparison approach to describe the assembly pathway for histone H1

PubMed Central

Contreras, Carlos; Villasana, Minaya; Hendzel, Michael J.

2018-01-01

Histones H1 or linker histones are highly dynamic proteins that diffuse throughout the cell nucleus and associate with chromatin (DNA and associated proteins). This binding interaction of histone H1 with the chromatin is thought to regulate chromatin organization and DNA accessibility to transcription factors and has been proven to involve a kinetic process characterized by a population that associates weakly with chromatin and rapidly dissociates and another population that resides at a binding site for up to several minutes before dissociating. When considering differences between these two classes of interactions in a mathematical model for the purpose of describing and quantifying the dynamics of histone H1, it becomes apparent that there could be several assembly pathways that explain the kinetic data obtained in living cells. In this work, we model these different pathways using systems of reaction-diffusion equations and carry out a model comparison analysis using FRAP (fluorescence recovery after photobleaching) experimental data from different histone H1 variants to determine the most feasible mechanism to explain histone H1 binding to chromatin. The analysis favors four different chromatin assembly pathways for histone H1 which share common features and provide meaningful biological information on histone H1 dynamics. We show, using perturbation analysis, that the explicit consideration of high- and low-affinity associations of histone H1 with chromatin in the favored assembly pathways improves the interpretation of histone H1 experimental FRAP data. To illustrate the results, we use one of the favored models to assess the kinetic changes of histone H1 after core histone hyperacetylation, and conclude that this post-transcriptional modification does not affect significantly the transition of histone H1 from a weakly bound state to a tightly bound state. PMID:29352283

Time-of-flights and traps: from the Histone Code to Mars.

PubMed

Cotter, Robert J; Swatkoski, Stepehen; Becker, Luann; Evans-Nguyen, Theresa

2010-01-01

Two very different analytical instruments are featured in this perspective paper on mass spectrometer design and development. The first instrument, based upon the curved-field reflectron developed in the Johns Hopkins Middle Atlantic Mass Spectrometry Laboratory, is a tandem time-of-flight mass spectrometer whose performance and practicality are illustrated by applications to a series of research projects addressing the acetylation, deacetylation and ADP-ribosylation of histone proteins. The chemical derivatization of lysine-rich, hyperacetylated histones as their deuteroacetylated analogs enables one to obtain an accurate quantitative assessment of the extent of acetylation at each site. Chemical acetylation of histone mixtures is also used to determine the lysine targets of sirtuins, an important class of histone deacetylases (HDACs), by replacing the deacetylated residues with biotin. Histone deacetylation by sirtuins requires the co-factor NAD+, as does the attachment of ADP-ribose. The second instrument, a low voltage and low power ion trap mass spectrometer known as the Mars Organic Mass Analyzer (MOMA), is a prototype for an instrument expected to be launched in 2018. Like the tandem mass spectrometer, it is also expected to have applicability to environmental and biological analyses and, ultimately, to clinical care.

Time-of-flights and traps: from the Histone Code to Mars*

PubMed Central

Swatkoski, Stephen; Becker, Luann; Evans-Nguyen, Theresa

2011-01-01

Two very different analytical instruments are featured in this perspective paper on mass spectrometer design and development. The first instrument, based upon the curved-field reflectron developed in the Johns Hopkins Middle Atlantic Mass Spectrometry Laboratory, is a tandem time-of-flight mass spectrometer whose performance and practicality are illustrated by applications to a series of research projects addressing the acetylation, deacetylation and ADP-ribosylation of histone proteins. The chemical derivatization of lysine-rich, hyperacetylated histones as their deuteroacetylated analogs enables one to obtain an accurate quantitative assessment of the extent of acetylation at each site. Chemical acetylation of histone mixtures is also used to determine the lysine targets of sirtuins, an important class of histone deacetylases (HDACs), by replacing the deacetylated residues with biotin. Histone deacetylation by sirtuins requires the co-factor NAD+, as does the attachment of ADP-ribose. The second instrument, a low voltage and low power ion trap mass spectrometer known as the Mars Organic Mass Analyzer (MOMA), is a prototype for an instrument expected to be launched in 2018. Like the tandem mass spectrometer, it is also expected to have applicability to environmental and biological analyses and, ultimately, to clinical care. PMID:20530839

A population based survey of ergonomic risk factors in Connecticut: distribution by industry, occupation, and demographics.

PubMed

Morse, Tim F; Warren, Nicholas; Dillon, Charles; Diva, Ulysses

2007-05-01

Risk factors for upper-extremity musculoskeletal disorders (MSD) include biomechanical factors (force, repetition, posture) and psychosocial factors (job stress). A population-based telephone survey of workers in Connecticut characterized these risk factors by industry, occupation, gender, and age. Risk factors were highly prevalent in the Connecticut workplace, but varied considerably by industry, occupation, gender, and age. Risk factors clustered based on (a) physically active occupations/industries (pushing/pulling, reaching, bent wrists, and tool use), (b) physically passive occupations/industries (static postures, stress, and computer use), and (c) repetitive motion exposures. Physically active patterns had the highest prevalence in construction/agriculture/mining, followed by (in order) wholesale/retail trade, utilities, manufacturing, services, government, and finance/insurance. Physically passive patterns tended to reverse this order, and repetitive motion followed a third pattern. Physically active risk factors were typically higher for males, though this varied by industry and occupation. All risk factors except for stress show a steady decrease with age. Almost 1,000,000 Connecticut workers are estimated to be exposed to repetitive work, bent wrists, and job stress. Workers in high exposure industries and occupations should be closely evaluated for risks, with outreach to industries for preventive ergonomic interventions as preferred to treatment for conditions that arise.

Core histone genes of Giardia intestinalis: genomic organization, promoter structure, and expression

PubMed Central

Yee, Janet; Tang, Anita; Lau, Wei-Ling; Ritter, Heather; Delport, Dewald; Page, Melissa; Adam, Rodney D; Müller, Miklós; Wu, Gang

2007-01-01

Background Giardia intestinalis is a protist found in freshwaters worldwide, and is the most common cause of parasitic diarrhea in humans. The phylogenetic position of this parasite is still much debated. Histones are small, highly conserved proteins that associate tightly with DNA to form chromatin within the nucleus. There are two classes of core histone genes in higher eukaryotes: DNA replication-independent histones and DNA replication-dependent ones. Results We identified two copies each of the core histone H2a, H2b and H3 genes, and three copies of the H4 gene, at separate locations on chromosomes 3, 4 and 5 within the genome of Giardia intestinalis, but no gene encoding a H1 linker histone could be recognized. The copies of each gene share extensive DNA sequence identities throughout their coding and 5' noncoding regions, which suggests these copies have arisen from relatively recent gene duplications or gene conversions. The transcription start sites are at triplet A sequences 1–27 nucleotides upstream of the translation start codon for each gene. We determined that a 50 bp region upstream from the start of the histone H4 coding region is the minimal promoter, and a highly conserved 15 bp sequence called the histone motif (him) is essential for its activity. The Giardia core histone genes are constitutively expressed at approximately equivalent levels and their mRNAs are polyadenylated. Competition gel-shift experiments suggest that a factor within the protein complex that binds him may also be a part of the protein complexes that bind other promoter elements described previously in Giardia. Conclusion In contrast to other eukaryotes, the Giardia genome has only a single class of core histone genes that encode replication-independent histones. Our inability to locate a gene encoding the linker histone H1 leads us to speculate that the H1 protein may not be required for the compaction of Giardia's small and gene-rich genome. PMID:17425802

Occupational pressure-targeting organisational factors to ameliorate occupational dysfunction.

PubMed

Loh, Siew Yim; Than, Winn; Quek, Kia Fatt

2011-12-01

Chronic pressure at work has debilitating impact on healthcare employers (e.g. reduced productivity, high costs, poor patient care) and on female healthcare employees (e.g. sickness, dysfunction). This paper highlights relationship at work as the key occupational source of work-stress which is organisational in nature. A cross-sectional study (n = 230) was conducted using the Pressure Management Inventory on several female dominated health professions within a large public hospital. Analysis of variance was used to show relationship between sources and outcome of pressure. Linear regressions were used to predict which sources of pressure (IV) was linked to the outcomes of occupational pressure (DV). The number one source of occupational pressure is relationships at work (i.e. with supervisors), and not workload. 'Relationship' is also the key predictor of several negative outcomes of pressure at work. Analysis of variance showed significant differences in two sources of pressures, i.e. Workload (P = 0.04) and Home-work balance (P = 0.03). This paper provides insights into the occupational pressure of women health professionals by highlighting the organisational sources of pressure and the implications for preventing occupational dysfunction secondary to stress at work.

Social and occupational factors associated with psychological wellbeing among occupational groups affected by disaster: a systematic review.

PubMed

Brooks, Samantha K; Dunn, Rebecca; Amlôt, Richard; Rubin, G James; Greenberg, Neil

2017-08-01

The psychological impact of disasters has been well-documented; less attention has been paid to factors affecting the wellbeing of those exposed to disasters as occupational groups. To conduct a systematic literature review identifying social and occupational factors affecting the wellbeing of disaster-exposed employees; to use these factors to identify recommendations for potential interventions. Four electronic literature databases were searched; reference lists of relevant papers were hand-searched. A total of 18 005 papers were found, 571 full texts were read and 36 included in the review. The psychological impact of disasters on employees was associated with pre-disaster factors (experience/training; income; life events/health; job satisfaction), peri-disaster factors (exposure; peri-traumatic experiences; perceptions of safety; injury), social factors (organisational support; social support generally) and post-disaster factors (impact on life). It is important to build a resilient workforce outside of a crisis. Pre-disaster training in recognising signs of distress, understanding vulnerability factors such as those described above, which may put certain employees at greater risk of distress and how to support colleagues may be useful. Further research into the effectiveness of post-disaster interventions is needed.

Occupational injuries: is job security a factor?

PubMed

Saha, Asim; Kulkarni, P K; Chaudhuri, R; Saiyed, H

2005-09-01

Although a large number of contributing factors of occupational injury causation are explored meticulously to explain the phenomenon of higher occupational injury occurrence in some subjects, it has remained a matter of controversy. In this study, an effort is made to explore whether job security has any contribution in explaining higher susceptibility of some workers. This was a retrospective occupational injury record study conducted in an industry of eastern India. Along with the study of injury records of 5 years, an interview was also conducted involving 726 workers (including permanent and temporary workers both) of the factory. Comparison was made between permanent and temporary workers by using the Mann-Whitney U-test and the chi-square test. A theoretical model of Poisson's distribution was used to compare between expected and real occurrence. Although two worker groups were very similar in relation to age, level of education, habits, and nature of work, accident frequency and severity rates were found to be significantly higher in temporary workers. This study concluded that the higher accident risk of the temporary workers might have been due to the less effective experience as well as due to lack of job security inherent in such workers.

Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2.

PubMed

Sancisi, Valentina; Gandolfi, Greta; Ambrosetti, Davide Carlo; Ciarrocchi, Alessia

2015-05-01

Aberrant reactivation of embryonic pathways occurs commonly in cancer. The transcription factor RUNX2 plays a fundamental role during embryogenesis and is aberrantly reactivated during progression and metastasization of different types of human tumors. In this study, we attempted to dissect the molecular mechanisms governing RUNX2 expression and its aberrant reactivation. We identified a new regulatory enhancer element, located within the RUNX2 gene, which is responsible for the activation of the RUNX2 promoter and for the regulation of its expression in cancer cells. Furthermore, we have shown that treatment with the anticancer compounds histone deacetylase inhibitor (HDACi) results in a profound inhibition of RUNX2 expression, which is determined by the disruption of the transcription-activating complex on the identified enhancer. These data envisage a possible targeting strategy to counteract the oncongenic function of RUNX2 in cancer cells and provide evidence that the cytotoxic activity of HDACi in cancer is not only dependent on the reactivation of silenced oncosuppressors but also on the repression of oncogenic factors that are necessary for survival and progression. ©2015 American Association for Cancer Research.

A Role for Histone Deacetylases in the Cellular and Behavioral Mechanisms Underlying Learning and Memory

ERIC Educational Resources Information Center

Mahgoub, Melissa; Monteggia, Lisa M.

2014-01-01

Histone deacetylases (HDACs) are a family of chromatin remodeling enzymes that restrict access of transcription factors to the DNA, thereby repressing gene expression. In contrast, histone acetyltransferases (HATs) relax the chromatin structure allowing for an active chromatin state and promoting gene transcription. Accumulating data have…

[Levels of awareness of occupational and general cardiovascular risk factors among metal industry employees].

PubMed

Gürdoğan, Muhammet; Paslı Gürdoğan, Eylem; Arı, Hasan; Ertürk, Mehmet; Genç, Ahmet; Uçar, Mehmet Fatih

2015-06-01

Long-term exposure to physical, chemical, ergonomic and psychosocial environmental factors may lead to occupational cardiovascular disease in metal industry employees. This study aimed to determine levels of knowledge levels regarding occupational and cardiovascular risk factors among metal industry employees. The study was conducted between 2nd and 6th June 2014 with the participation of 82 employees. All were working in a medium-sized workplace in the metal industry. Data were collected by means of a questionnaire, which included socio-demographic characteristics and occupational cardiovascular risk factors, and a scale developed by Arıkan et al. to measure awareness levels of risk factors for cardiovascular diseases (CARRF-KL). The mean age of employees was 39.97±8.44. Of the participants, 58.5% stated that they had knowledge on cardiac disease risk factors. The mean CARRF-KL score was found to be 18.65±4.04. The percentage of employees stating that they had no knowledge on the occupational risks for such diseases was 79.3%, while 19.5% stated that job stress caused cardiac diseases. One individual (1.2%) stated that one of the chemical solvents used in the working environment was a risk factor. Although awareness among metal industry employees of cardiovascular risk factors was above average, it was determined that they do not have adequate information on occupational risk factors. Prolonged and unprotected levels exposure to environmental factors constitute a risk for cardiovascular disease. This information is important for the development of preventive cardiology.

The elusive structural role of ubiquitinated histones.

PubMed

Moore, Susan C; Jason, Laure; Ausió, Juan

2002-01-01

It is increasingly apparent that histone posttranslational modifications are important in chromatin structure and dynamics. However, histone ubiquitination has received little attention. Histones H1, H3, H2A, and H2B can be ubiquitinated in vivo, but the most prevalent are uH2A and uH2B. The size of this modification suggests some sort of structural impact. Physiological observations suggest that ubiquitinated histones may have multiple functions and structural effects. Ubiquitinated histones have been correlated with transcriptionally active DNA, implying that it may prevent chromatin folding or help maintain an open conformation. Also, in some organisms during spermiogenesis, a process involving extensive chromatin remodeling, uH2A levels increase just prior to histone replacement by protamines. Determination of chromatin's structural changes resulting from histone ubiquitination is therefore important. Recent work using reconstituted nucleosomes and chromatin fibers containing uH2A indicate that in the absence of linker histones, ubiquitination has little structural impact. DNase I digests and analytical ultracentrifugation of reconstituted ubiquitinated nucleosomes show no structural differences. Solubility assays using reconstituted chromatin fibers in the presence of divalent ions demonstrate that uH2A fibers are slightly more prone to aggregation than controls, and analytical ultracentrifugation results with different MgCl2 and NaCl concentrations determined that chromatin folding is not affected by this modification. Additional work to assess possible synergistic affects with histone acetylation also precludes any structural implications. Protamine displacement experiments concluded that the presence of uH2A does not significantly affect the ability of the protamines to displace histones. In addition, uH2A does not interfere with histone H1 binding to the nucleosome. While work with uH2B remains insufficient to come to any definitive conclusions about its

Newly graduated nurses' occupational commitment and its associations with professional competence and work-related factors.

PubMed

Numminen, Olivia; Leino-Kilpi, Helena; Isoaho, Hannu; Meretoja, Riitta

2016-01-01

To explore newly graduated nurses' occupational commitment and its associations with their self-assessed professional competence and other work-related factors. As a factor affecting nurse turnover, newly graduated nurses' occupational commitment and its associations with work-related factors needs exploring to retain adequate workforce. Nurses' commitment has mainly been studied as organisational commitment, but newly graduated nurses' occupational commitment and its association with work-related factors needs further studying. This study used descriptive, cross-sectional, correlation design. A convenience sample of 318 newly graduated nurses in Finland participated responding to an electronic questionnaire. Statistical software, NCSS version 9, was used in data analysis. Frequencies, percentages, ranges, means and standard deviations summarised the data. Multivariate Analyses of Variance estimated associations between occupational commitment and work-related variables. IBM SPSS Amos version 22 estimated the model fit of Occupational Commitment Scale and Nurse Competence Scale. Newly graduated nurses' occupational commitment was good, affective commitment reaching the highest mean score. There was a significant difference between the nurse groups in favour of nurses at higher competence levels in all subscales except in limited alternatives occupational commitment. Multivariate analyses revealed significant associations between subscales of commitment and competence, turnover intentions, job satisfaction, earlier professional education and work sector, competence counting only through affective dimension. The association between occupational commitment and low turnover intentions and satisfaction with nursing occupation was strong. Higher general competence indicated higher overall occupational commitment. Managers' recognition of the influence of all dimensions of occupational commitment in newly graduated nurses' professional development is important. Follow

[Profiles of factors enhancing teachers' occupational wellbeing and their use in health promoting schools].

PubMed

Woynarowska-Sołdan, Magdalena; Weziak-Białowolska, Dorota

2012-01-01

The aim of this article is to present the results of survey on general occupational being and factors contributing to the enhancement of teachers' occupational wellbeing. The authors also address the issue how to work out, analyze, present and use the survey results in health promotion at schools. Teachers of four selected health promoting schools (HPS) were surveyed and the results were analyzed. The Factors Enhancing Teachers's Occupational Wellbeing Scale was used. This instrument consisted of 45 statements on 5 subscales (working conditions, teachers' community, students' and parents' community, organization and workload, professional competences). They were measured from two points of view, the assessment of a current situation and the assessment of needs for the improvement. The scale was preceded by questions concerning the assessment of general occupational being and the assessment of general occupational being of other teachers at school. The self-assessment of the respondents' own and other teachers' occupational being was positive. The current situation related to factors influencing teachers' wellbeing was recognized by teachers as rather good and the need for change was rather low. There were differences between schools in the majority of analyzed factors. An easy method of analyzing data as numerical values and graphic profiles was proposed to be used in HPS. Factors influencing teachers' occupational wellbeing differed between schools. The results of their assessment should be analyzed in each school taking account of its individual context. The proposed instrument and method of data analysis are useful in the planning of teachers' health promotion projects, diagnosis of the initial status ("pre-test") and evaluation of their outcomes ("post-test").

Occupational Stress and Cardiovascular Risk Factors in High-Ranking Government Officials and Office Workers

PubMed Central

Mirmohammadi, Seyyed Jalil; Taheri, Mahmoud; Mehrparvar, Amir Houshang; Heydari, Mohammad; Saadati Kanafi, Ali; Mostaghaci, Mehrdad

2014-01-01

Background: Cardiovascular diseases are among the most important sources of mortality and morbidity, and have a high disease burden. There are some major well-known risk factors, which contribute to the development of these diseases. Occupational stress is caused due to imbalance between job demands and individual’s ability, and it has been implicated as an etiology for cardiovascular diseases. Objectives: This study was conducted to evaluate the cardiovascular risk factors and different dimensions of occupational stress in high-ranking government officials, comparing an age and sex-matched group of office workers with them. Patients and Methods: We invited 90 high-ranking officials who managed the main governmental offices in a city, and 90 age and sex-matched office workers. The subjects were required to fill the occupational role questionnaire (Osipow) which evaluated their personal and medical history as well as occupational stress. Then, we performed physical examination and laboratory tests to check for cardiovascular risk factors. Finally, the frequency of cardiovascular risk factors and occupational stress of two groups were compared. Results: High-ranking officials in our study had less work experience in their current jobs and smoked fewer pack-years of cigarette, but they had higher waist and hip circumference, higher triglyceride level, more stress from role overload and responsibility, and higher total stress score. Our group of office workers had more occupational stress because of role ambiguity and insufficiency, but their overall job stress was less than officials. Conclusions: The officials have higher scores in some dimensions of occupational stress and higher overall stress score. Some cardiovascular risk factors were also more frequent in managers. PMID:25389469

Obesity Prevalence by Occupation in Washington State, Behavioral Risk Factor Surveillance System

PubMed Central

Lu, Dayu; Fan, Z. Joyce

2014-01-01

Introduction Data that estimate the prevalence of and risk factors for worker obesity by occupation are generally unavailable and could inform the prioritization of workplace wellness programs. The aims of this study were to estimate the prevalence of obesity by occupation, examine the association of occupational physical activity and a range of health behaviors with obesity, and identify occupations in which workers are at high risk of obesity in Washington State. Methods We conducted descriptive and multivariable analyses among 37,626 employed Washington State respondents using the Behavioral Risk Factor Surveillance System in odd numbered years, from 2003 through 2009. We estimated prevalence and prevalence ratios (PRs) by occupational groups adjusting for demographics, occupational physical activity level, smoking, fruit and vegetable consumption, and leisure-time physical activity (LPTA). Results Overall obesity prevalence was 24.6% (95% confidence interval [CI], 24.0–25.1). Workers in protective services were 2.46 (95% CI, 1.72–3.50) times as likely to be obese as workers in health diagnosing occupations. Compared with their counterparts, workers who consumed adequate amounts of fruits and vegetables and had adequate LTPA were significantly less likely to be obese (PR = 0.91; 95% CI, 0.86–0.97 and PR = 0.63; 95% CI, 0.60–0.67, respectively). Workers with physically demanding occupational physical activity had a lower PR of obesity (PR = 0.83; 95% CI, 0.78–0.88) than those with nonphysically demanding occupational physical activity. Conclusion Obesity prevalence and health risk behaviors vary substantially by occupation. Employers, policy makers, and health promotion practitioners can use our results to target and prioritize workplace obesity prevention and health behavior promotion programs. PMID:24406093

The histone codes for meiosis.

PubMed

Wang, Lina; Xu, Zhiliang; Khawar, Muhammad Babar; Liu, Chao; Li, Wei

2017-09-01

Meiosis is a specialized process that produces haploid gametes from diploid cells by a single round of DNA replication followed by two successive cell divisions. It contains many special events, such as programmed DNA double-strand break (DSB) formation, homologous recombination, crossover formation and resolution. These events are associated with dynamically regulated chromosomal structures, the dynamic transcriptional regulation and chromatin remodeling are mainly modulated by histone modifications, termed 'histone codes'. The purpose of this review is to summarize the histone codes that are required for meiosis during spermatogenesis and oogenesis, involving meiosis resumption, meiotic asymmetric division and other cellular processes. We not only systematically review the functional roles of histone codes in meiosis but also discuss future trends and perspectives in this field. © 2017 Society for Reproduction and Fertility.

Boric acid inhibits embryonic histone deacetylases: A suggested mechanism to explain boric acid-related teratogenicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Di Renzo, Francesca; Cappelletti, Graziella; Broccia, Maria L.

2007-04-15

Histone deacetylases (HDAC) control gene expression by changing histonic as well as non histonic protein conformation. HDAC inhibitors (HDACi) are considered to be among the most promising drugs for epigenetic treatment for cancer. Recently a strict relationship between histone hyperacetylation in specific tissues of mouse embryos exposed to two HDACi (valproic acid and trichostatin A) and specific axial skeleton malformations has been demonstrated. The aim of this study is to verify if boric acid (BA), that induces in rodents malformations similar to those valproic acid and trichostatin A-related, acts through similar mechanisms: HDAC inhibition and histone hyperacetylation. Pregnant mice weremore » treated intraperitoneally with a teratogenic dose of BA (1000 mg/kg, day 8 of gestation). Western blot analysis and immunostaining were performed with anti hyperacetylated histone 4 (H4) antibody on embryos explanted 1, 3 or 4 h after treatment and revealed H4 hyperacetylation at the level of somites. HDAC enzyme assay was performed on embryonic nuclear extracts. A significant HDAC inhibition activity (compatible with a mixed type partial inhibition mechanism) was evident with BA. Kinetic analyses indicate that BA modifies substrate affinity by a factor {alpha} = 0.51 and maximum velocity by a factor {beta} = 0.70. This work provides the first evidence for HDAC inhibition by BA and suggests such a molecular mechanism for the induction of BA-related malformations.« less

Occupational accidents in the Netherlands: incidence, mental harm, and their relationship with psychosocial factors at work.

PubMed

van der Klauw, Marloes; Hengel, Karen Oude; Roozeboom, Maartje Bakhuys; Koppes, Lando L; Venema, Anita

2016-01-01

This study investigated the incidence of mental harm due to occupational accidents and the relation between psychosocial factors at work and the occurrence of occupational accidents in the Netherlands for the construction industry and health and welfare sector. Analyses revealed that occupational accidents in the construction industry more often involved physical harm, whereas accidents in the health and welfare sector relatively more often resulted in mental harm, in comparison to other sectors. Results showed that psychosocial factors were associated with occupational accidents in both sectors. For the construction industry, high time pressure and exposure to violence and harassment by colleagues or supervisors were associated with occupational accidents. For the health and welfare sector, low autonomy and exposure to violence and harassment by colleagues or supervisors or by people outside the organization were associated with occupational accidents. The present paper stresses the importance of also taking psychological consequences and psychosocial factors at work into account in assessing the occurrence of occupational accidents.

Dynamic motif occupancy (DynaMO) analysis identifies transcription factors and their binding sites driving dynamic biological processes.

PubMed

Kuang, Zheng; Ji, Zhicheng; Boeke, Jef D; Ji, Hongkai

2018-01-09

Biological processes are usually associated with genome-wide remodeling of transcription driven by transcription factors (TFs). Identifying key TFs and their spatiotemporal binding patterns are indispensable to understanding how dynamic processes are programmed. However, most methods are designed to predict TF binding sites only. We present a computational method, dynamic motif occupancy analysis (DynaMO), to infer important TFs and their spatiotemporal binding activities in dynamic biological processes using chromatin profiling data from multiple biological conditions such as time-course histone modification ChIP-seq data. In the first step, DynaMO predicts TF binding sites with a random forests approach. Next and uniquely, DynaMO infers dynamic TF binding activities at predicted binding sites using their local chromatin profiles from multiple biological conditions. Another landmark of DynaMO is to identify key TFs in a dynamic process using a clustering and enrichment analysis of dynamic TF binding patterns. Application of DynaMO to the yeast ultradian cycle, mouse circadian clock and human neural differentiation exhibits its accuracy and versatility. We anticipate DynaMO will be generally useful for elucidating transcriptional programs in dynamic processes. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Rapid divergence of histones in Hydrozoa (Cnidaria) and evolution of a novel histone involved in DNA damage response in hydra.

PubMed

Reddy, Puli Chandramouli; Ubhe, Suyog; Sirwani, Neha; Lohokare, Rasika; Galande, Sanjeev

2017-08-01

Histones are fundamental components of chromatin in all eukaryotes. Hydra, an emerging model system belonging to the basal metazoan phylum Cnidaria, provides an ideal platform to understand the evolution of core histone components at the base of eumetazoan phyla. Hydra exhibits peculiar properties such as tremendous regenerative capacity, lack of organismal senescence and rarity of malignancy. In light of the role of histone modifications and histone variants in these processes it is important to understand the nature of histones themselves and their variants in hydra. Here, we report identification of the complete repertoire of histone-coding genes in the Hydra magnipapillata genome. Hydra histones were classified based on their copy numbers, gene structure and other characteristic features. Genomic organization of canonical histone genes revealed the presence of H2A-H2B and H3-H4 paired clusters in high frequency and also a cluster with all core histones along with H1. Phylogenetic analysis of identified members of H2A and H2B histones suggested rapid expansion of these groups in Hydrozoa resulting in the appearance of unique subtypes. Amino acid sequence level comparisons of H2A and H2B forms with bilaterian counterparts suggest the possibility of a highly mobile nature of nucleosomes in hydra. Absolute quantitation of transcripts confirmed the high copy number of histones and supported the canonical nature of H2A. Furthermore, functional characterization of H2A.X.1 and a unique variant H2A.X.2 in the gastric region suggest their role in the maintenance of genome integrity and differentiation processes. These findings provide insights into the evolution of histones and their variants in hydra. Copyright © 2017 Elsevier GmbH. All rights reserved.

Histone deacetylase inhibitor belinostat represses survivin expression through reactivation of transforming growth factor beta (TGFbeta) receptor II leading to cancer cell death.

PubMed

Chowdhury, Sanjib; Howell, Gillian M; Teggart, Carol A; Chowdhury, Aparajita; Person, Jonathan J; Bowers, Dawn M; Brattain, Michael G

2011-09-02

Survivin is a cancer-associated gene that functions to promote cell survival, cell division, and angiogenesis and is a marker of poor prognosis. Histone deacetylase inhibitors induce apoptosis and re-expression of epigenetically silenced tumor suppressor genes in cancer cells. In association with increased expression of the tumor suppressor gene transforming growth factor β receptor II (TGFβRII) induced by the histone deacetylase inhibitor belinostat, we observed repressed survivin expression. We investigated the molecular mechanisms involved in survivin down-regulation by belinostat downstream of reactivation of TGFβ signaling. We identified two mechanisms. At early time points, survivin protein half-life was decreased with its proteasomal degradation. We observed that belinostat activated protein kinase A at early time points in a TGFβ signaling-dependent mechanism. After longer times (48 h), survivin mRNA was also decreased by belinostat. We made the novel observation that belinostat mediated cell death through the TGFβ/protein kinase A signaling pathway. Induction of TGFβRII with concomitant survivin repression may represent a significant mechanism in the anticancer effects of this drug. Therefore, patient populations exhibiting high survivin expression with epigenetically silenced TGFβRII might potentially benefit from the use of this histone deacetylase inhibitor.

Occupation as a risk factor for hypertensive disorders of pregnancy.

PubMed

Bilhartz, Terry D; Bilhartz, Patty

2013-02-01

Hypertensive disorders of pregnancy (HDP) are leading causes of morbidity and mortality and have been rising in incidence. Little is known about the effects of worker classifications on HDP. This large-scale study examines associations between occupational classifications and HDP. We examined 385,537 Texas Electronic Registrar Birth Registration 2005 birth certificates. Maternal occupations were coded using the Standard Occupational Classification (SOC). Crude and adjusted risks for HDP among working women within occupational groupings were analyzed and compared with risks of nonemployed women. The risk of developing HDP varies across SOC occupational classifications. After controlling for known confounders, women employed in business, management, and the legal and social services, teaching, counseling, and healthcare professions are at higher risk for developing HDP than women employed in support industries, such as food preparation, housekeeping, cosmetic and personal care services, or nonemployed women. Women employed in computer, engineering, architectural, and scientific occupations also carry greater risks, although these increased risks do not affect women of normal weight. Worker classification is an independent risk factor for HDP. Additional work must be done to examine the complex interactions among individual maternal genetics, biology, and physical and mental abilities and how they affect adverse health outcomes. Examining job stressors may shed light on these occupational variations and their potential HDP associations. Strategies to mitigate job stressors in the workplace should be considered.

A multifaceted role for MOF histone modifying factor in genome maintenance.

PubMed

Mujoo, Kalpana; Hunt, Clayton R; Horikoshi, Nobuo; Pandita, Tej K

2017-01-01

MOF (males absent on the first) was initially identified as a dosage compensation factor in Drosophila that acetylates lysine 16 of histone H4 (H4K16ac) and increased gene transcription from the single copy male X-chromosome. In humans, however, the ortholog of Drosophila MOF has been shown to interact with a range of proteins that extend its potential significance well beyond transcription. For example, recent results indicate MOF is an upstream regulator of the ATM (ataxia-telangiectasia mutated) protein, the loss of which is responsible for ataxia telangiectasia (AT). ATM is a key regulatory kinase that interacts with and phosphorylates multiple substrates that influence critical, cell-cycle control and DNA damage repair pathways in addition to other pathways. Thus, directly or indirectly, MOF may be involved in a wide range of cellular functions. This review will focus on the contribution of MOF to cellular DNA repair and new results that are beginning to examine the in vivo physiological role of MOF. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Epigenetics mediate environment : gene effects on occupational sensitization.

PubMed

Pacheco, Karin A

2012-04-01

Epigenetics is the study of stable modifications of fixed genomes that direct which genes are expressed and which are silenced. Epigenetic changes are modulated by environmental exposures, making epigenetics the interface between genes and environment. This has particular relevance in understanding the effect of occupational exposures on the expression of allergic disease. The goal of this review is to describe how epigenetic changes affect transcription potential, and to examine more closely the effect of specific environmental and occupational exposures on epigenetic variations that alter allergy gene transcripts and the inflammatory milieu. Gene transcription is activated when specific CpG sites are demethylated and histones are acetylated, and, conversely, silenced when sites are methylated and histones deacetylated. The development of Th1 and Th2 phenotypes, and expression of Treg cells, are now known to be modulated by epigenetic mechanisms. Workplace exposures such as tobacco smoke, particulates, diesel exhaust, polyaromatic hydrocarbons, ozone, and endotoxin, among others, suppress Treg development, and enhance expression of inflammatory cytokines and allergic phenotypes by epigenetic means. Epigenetic manipulation to open and close transcription sites provides flexibility of gene expression in response to changing environmental cues. It may also be the window whereby allergic disease in the workplace can be reduced by targeted environmental interventions.

Distinct self-interaction domains promote Multi Sex Combs accumulation in and formation of the Drosophila histone locus body

PubMed Central

Terzo, Esteban A.; Lyons, Shawn M.; Poulton, John S.; Temple, Brenda R. S.; Marzluff, William F.; Duronio, Robert J.

2015-01-01

Nuclear bodies (NBs) are structures that concentrate proteins, RNAs, and ribonucleoproteins that perform functions essential to gene expression. How NBs assemble is not well understood. We studied the Drosophila histone locus body (HLB), a NB that concentrates factors required for histone mRNA biosynthesis at the replication-dependent histone gene locus. We coupled biochemical analysis with confocal imaging of both fixed and live tissues to demonstrate that the Drosophila Multi Sex Combs (Mxc) protein contains multiple domains necessary for HLB assembly. An important feature of this assembly process is the self-interaction of Mxc via two conserved N-terminal domains: a LisH domain and a novel self-interaction facilitator (SIF) domain immediately downstream of the LisH domain. Molecular modeling suggests that the LisH and SIF domains directly interact, and mutation of either the LisH or the SIF domain severely impairs Mxc function in vivo, resulting in reduced histone mRNA accumulation. A region of Mxc between amino acids 721 and 1481 is also necessary for HLB assembly independent of the LisH and SIF domains. Finally, the C-terminal 195 amino acids of Mxc are required for recruiting FLASH, an essential histone mRNA-processing factor, to the HLB. We conclude that multiple domains of the Mxc protein promote HLB assembly in order to concentrate factors required for histone mRNA biosynthesis. PMID:25694448

Factors influencing occupancy of nest cavities in recently burned forests

USGS Publications Warehouse

Saab, V.A.; Dudley, J.; Thompson, W.L.

2004-01-01

Recently burned forests in western North America provide nesting habitat for many species of cavity-nesting birds. However, little is understood about the time frame and the variables affecting occupancy of postfire habitats by these birds. We studied factors influencing the occupancy and reuse of nest cavities from 1-7 years after fire in two burned sites of western Idaho during 1994-1999. Tree cavities were used for nesting by 12 species of cavity nesters that were classified by the original occupant (strong excavator, weak excavator, or nonexcavator) of 385 nest cavities. We used logistic regression to model cavity occupancy by strong excavators (n = 575 trials) and weak excavators (n = 206 trials). Year after fire had the greatest influence on occupancy of nest cavities for both groups, while site of the burn was secondarily important in predicting occupancy by strong excavators and less important for weak excavators. Predicted probability of cavity occupancy was highest during the early years (1-4) after fire, declined over time (5-7 years after fire), and varied by site, with a faster decline in the smaller burned site with a greater mosaic of unburned forest. Closer proximity and greater interspersion of unburned forest (15% unburned) may have allowed a quicker recolonization by nest predators into the smaller burn compared to the larger burn with few patches of unburned forest (4% unburned). In combination with time and space effects, the predicted probability of cavity occupancy was positively affected by tree and nest heights for strong and weak excavators, respectively.

Histone Deacetylase-1 Is Enriched at the Platelet-derived Growth Factor-D Promoter in Response to Interleukin-1β and Forms a Cytokine-inducible Gene-silencing Complex with NF-κB p65 and Interferon Regulatory Factor-1*

PubMed Central

Liu, Mary Y.; Khachigian, Levon M.

2009-01-01

Understanding the mechanisms governing cytokine control of growth factor expression in smooth muscle cells would provide invaluable insight into the molecular regulation of vascular phenotypes and create future opportunities for therapeutic intervention. Here, we report that the proinflammatory cytokine interleukin (IL)-1β suppresses platelet-derived growth factor (PDGF)-D promoter activity and mRNA and protein expression in smooth muscle cells. NF-κB p65, induced by IL-1β, interacts with a novel element in the PDGF-D promoter and inhibits PDGF-D transcription. Interferon regulatory factor-1 (IRF-1) is also induced by IL-1β and binds to a different element upstream in the promoter. Immunoprecipitation and chromatin immunoprecipitation experiments showed that IL-1β stimulates p65 interaction with IRF-1 and the accumulation of both factors at the PDGF-D promoter. Mutation of the IRF-1 and p65 DNA-binding elements relieved the promoter from IL-1β-mediated repression. PDGF-D repression by IL-1β involves histone deacetylation and interaction of HDAC-1 with IRF-1 and p65. HDAC-1 small interfering RNA ablates complex formation with IRF-1 and p65 and abrogates IRF-1 and p65 occupancy of the PDGF-D promoter. Thus, HDAC-1 is enriched at the PDGF-D promoter in cells exposed to IL-1β and forms a cytokine-inducible gene-silencing complex with p65 and IRF-1. PMID:19843519

Exposure to occupational therapy as a factor influencing recruitment to the profession.

PubMed

Byrne, Nicole

2015-08-01

This article provides insight into the impact that exposure to an occupational therapist, in personal capacity or via a professional interaction, has on the decision to enter an occupational therapy undergraduate programme. A quantitative survey was completed by 139 occupational therapy students. The survey tool focussed on the students' exposure to a range of allied health professions (e.g. occupational therapy, physiotherapy, psychology) and investigated how exposure to occupational therapy had influenced their decision to enter the programme. The results indicated that over 70% of respondents had personal professional exposure to occupational therapy prior to making a career decision. Exposure most frequently involved occupational therapy intervention of a friend or family member. The majority of students who had professional exposure to occupational therapy (e.g. family, self, friend received occupational therapy) identified that it was the most influential factor in their career choice. Forty per cent of the occupational therapy students did not enter the programme straight from school and the influence of 'working with an occupational therapist' was noteworthy for mature aged students. Occupational therapists need to consider that every interaction they have with the community provides valuable information regarding the profession and gives insight into occupational therapy as a potential career path for other people. Additionally, the current research identifies there were differences in the impact, type and number of exposures for different student groups, and this potentially offers some insight into ways in which occupational therapy could target specific groups within the community to increase future diversity in the profession. © 2015 Occupational Therapy Australia.

Drosophila Symplekin localizes dynamically to the histone locus body and tricellular junctions.

PubMed

Tatomer, Deirdre C; Rizzardi, Lindsay F; Curry, Kaitlin P; Witkowski, Alison M; Marzluff, William F; Duronio, Robert J

2014-01-01

The scaffolding protein Symplekin is part of multiple complexes involved in generating and modifying the 3' end of mRNAs, including cleavage-polyadenylation, histone pre-mRNA processing and cytoplasmic polyadenylation. To study these functions in vivo, we examined the localization of Symplekin during development and generated mutations of the Drosophila Symplekin gene. Mutations in Symplekin that reduce Symplekin protein levels alter the efficiency of both poly A(+) and histone mRNA 3' end formation resulting in lethality or sterility. Histone mRNA synthesis takes place at the histone locus body (HLB) and requires a complex composed of Symplekin and several polyadenylation factors that associates with the U7 snRNP. Symplekin is present in the HLB in the early embryo when Cyclin E/Cdk2 is active and histone genes are expressed and is absent from the HLB in cells that have exited the cell cycle. During oogenesis, Symplekin is preferentially localized to HLBs during S-phase in endoreduplicating follicle cells when histone mRNA is synthesized. After the completion of endoreplication, Symplekin accumulates in the cytoplasm, in addition to the nucleoplasm, and localizes to tricellular junctions of the follicle cell epithelium. This localization depends on the RNA binding protein ypsilon schachtel. CPSF-73 and a number of mRNAs are localized at this same site, suggesting that Symplekin participates in cytoplasmic polyadenylation at tricellular junctions.

3′-End processing of histone pre-mRNAs in Drosophila: U7 snRNP is associated with FLASH and polyadenylation factors

PubMed Central

Sabath, Ivan; Skrajna, Aleksandra; Yang, Xiao-cui; Dadlez, Michał; Marzluff, William F.; Dominski, Zbigniew

2013-01-01

3′-End cleavage of animal replication-dependent histone pre-mRNAs is controlled by the U7 snRNP. Lsm11, the largest component of the U7-specific Sm ring, interacts with FLASH, and in mammalian nuclear extracts these two proteins form a platform that recruits the CPSF73 endonuclease and other polyadenylation factors to the U7 snRNP. FLASH is limiting, and the majority of the U7 snRNP in mammalian extracts exists as a core particle consisting of the U7 snRNA and the Sm ring. Here, we purified the U7 snRNP from Drosophila nuclear extracts and characterized its composition by mass spectrometry. In contrast to the mammalian U7 snRNP, a significant fraction of the Drosophila U7 snRNP contains endogenous FLASH and at least six subunits of the polyadenylation machinery: symplekin, CPSF73, CPSF100, CPSF160, WDR33, and CstF64. The same composite U7 snRNP is recruited to histone pre-mRNA for 3′-end processing. We identified a motif in Drosophila FLASH that is essential for the recruitment of the polyadenylation complex to the U7 snRNP and analyzed the role of other factors, including SLBP and Ars2, in 3′-end processing of Drosophila histone pre-mRNAs. SLBP that binds the upstream stem–loop structure likely recruits a yet-unidentified essential component(s) to the processing machinery. In contrast, Ars2, a protein previously shown to interact with FLASH in mammalian cells, is dispensable for processing in Drosophila. Our studies also demonstrate that Drosophila symplekin and three factors involved in cleavage and polyadenylation—CPSF, CstF, and CF Im—are present in Drosophila nuclear extracts in a stable supercomplex. PMID:24145821

Core Histones and HIRIP3, a Novel Histone-Binding Protein, Directly Interact with WD Repeat Protein HIRA

PubMed Central

Lorain, Stéphanie; Quivy, Jean-Pierre; Monier-Gavelle, Frédérique; Scamps, Christine; Lécluse, Yann; Almouzni, Geneviève; Lipinski, Marc

1998-01-01

The human HIRA gene has been named after Hir1p and Hir2p, two corepressors which together appear to act on chromatin structure to control gene transcription in Saccharomyces cerevisiae. HIRA homologs are expressed in a regulated fashion during mouse and chicken embryogenesis, and the human gene is a major candidate for the DiGeorge syndrome and related developmental disorders caused by a reduction to single dose of a fragment of chromosome 22q. Western blot analysis and double-immunofluorescence experiments using a specific antiserum revealed a primary nuclear localization of HIRA. Similar to Hir1p, HIRA contains seven amino-terminal WD repeats and probably functions as part of a multiprotein complex. HIRA and core histone H2B were found to physically interact in a yeast double-hybrid protein interaction trap, in GST pull-down assays, and in coimmunoprecipitation experiments performed from cellular extracts. In vitro, HIRA also interacted with core histone H4. H2B- and H4-binding domains were overlapping but distinguishable in the carboxy-terminal region of HIRA, and the region for HIRA interaction was mapped to the amino-terminal tail of H2B and the second α helix of H4. HIRIP3 (HIRA-interacting protein 3) is a novel gene product that was identified from its HIRA-binding properties in the yeast protein interaction trap. In vitro, HIRIP3 directly interacted with HIRA but also with core histones H2B and H3, suggesting that a HIRA-HIRIP3-containing complex could function in some aspects of chromatin and histone metabolism. Insufficient production of HIRA, which we report elsewhere interacts with homeodomain-containing DNA-binding factors during mammalian embryogenesis, could perturb the stoichiometric assembly of multimolecular complexes required for normal embryonic development. PMID:9710638

Silencing of IFN-stimulated gene transcription is regulated by histone H1 and its chaperone TAF-I

PubMed Central

Kadota, Shinichi; Nagata, Kyosuke

2014-01-01

Chromatin structure and its alteration play critical roles in the regulation of transcription. However, the transcriptional silencing mechanism with regard to the chromatin structure at an unstimulated state of the interferon (IFN)-stimulated gene (ISG) remains unclear. Here we investigated the role of template activating factor-I (TAF-I, also known as SET) in ISG transcription. Knockdown (KD) of TAF-I increased ISG transcript and simultaneously reduced the histone H1 level on the ISG promoters during the early stages of transcription after IFN stimulation from the unstimulated state. The transcription factor levels on the ISG promoters were increased in TAF-I KD cells only during the early stages of transcription. Furthermore, histone H1 KD also increased ISG transcript. TAF-I and histone H1 double KD did not show the additive effect in ISG transcription, suggesting that TAF-I and histone H1 may act on the same regulatory pathway to control ISG transcription. In addition, TAF-I KD and histone H1 KD affected the chromatin structure near the ISG promoters. On the basis of these findings, we propose that TAF-I and its target histone H1 are key regulators of the chromatin structure at the ISG promoter to maintain the silent state of ISG transcription. PMID:24878923

Histone deacetylase 3 (HDAC 3) as emerging drug target in NF-κB-mediated inflammation

PubMed Central

Leus, Niek G.J.; Zwinderman, Martijn R.H.; Dekker, Frank J.

2016-01-01

Activation of inflammatory gene expression is regulated, among other factors, by post-translational modifications of histone proteins. The most investigated type of histone modifications are lysine acetylations. Histone deacetylases (HDACs) remove acetylations from lysines, thereby influencing (inflammatory) gene expression. Intriguingly, apart from histones, HDACs also target non-histone proteins. The nuclear factor κB (NF-κB) pathway is an important regulator in the expression of numerous inflammatory genes, and acetylation plays a crucial role in regulating its responses. Several studies have shed more light on the role of HDAC 1-3 in inflammation with a particular pro-inflammatory role for HDAC 3. Nevertheless, the HDAC-NF-κB interactions in inflammatory signalling have not been fully understood. An important challenge in targeting the regulatory role of HDACs in the NF-κB pathway is the development of highly potent small molecules that selectively target HDAC iso-enzymes. This review focuses on the role of HDAC 3 in (NF-κB-mediated) inflammation and NF-κB lysine acetylation. In addition, we address the application of frequently used small molecule HDAC inhibitors as an approach to attenuate inflammatory responses, and their potential as novel therapeutics. Finally, recent progress and future directions in medicinal chemistry efforts aimed at HDAC 3-selective inhibitors are discussed. PMID:27371876

Factors Associated With Success in an Occupational Rehabilitation Program for Work-Related Musculoskeletal Disorders

PubMed Central

Hardison, Mark E.

2017-01-01

Work-related musculoskeletal disorders are a significant burden; however, no consensus has been reached on how to maximize occupational rehabilitation programs for people with these disorders, and the impact of simulating work tasks as a mode of intervention has not been well examined. In this retrospective cohort study, the authors used logistic regression to identify client and program factors predicting success for 95 clients in a general occupational rehabilitation program and 71 clients in a comprehensive occupational rehabilitation program. The final predictive model for general rehabilitation included gender, number of sessions completed, and performance of work simulation activities. Maximum hours per session was the only significant predictor of success in the comprehensive rehabilitation program. This study identifies new factors associated with success in occupational rehabilitation, specifically highlighting the importance of intensity (i.e., session length and number of sessions) of therapy and occupation-based activities for this population. PMID:28027046

Growth-Phase-Specific Modulation of Cell Morphology and Gene Expression by an Archaeal Histone Protein.

PubMed

Dulmage, Keely A; Todor, Horia; Schmid, Amy K

2015-09-08

In all three domains of life, organisms use nonspecific DNA-binding proteins to compact and organize the genome as well as to regulate transcription on a global scale. Histone is the primary eukaryotic nucleoprotein, and its evolutionary roots can be traced to the archaea. However, not all archaea use this protein as the primary DNA-packaging component, raising questions regarding the role of histones in archaeal chromatin function. Here, quantitative phenotyping, transcriptomic, and proteomic assays were performed on deletion and overexpression mutants of the sole histone protein of the hypersaline-adapted haloarchaeal model organism Halobacterium salinarum. This protein is highly conserved among all sequenced haloarchaeal species and maintains hallmark residues required for eukaryotic histone functions. Surprisingly, despite this conservation at the sequence level, unlike in other archaea or eukaryotes, H. salinarum histone is required to regulate cell shape but is not necessary for survival. Genome-wide expression changes in histone deletion strains were global, significant but subtle in terms of fold change, bidirectional, and growth phase dependent. Mass spectrometric proteomic identification of proteins from chromatin enrichments yielded levels of histone and putative nucleoid-associated proteins similar to those of transcription factors, consistent with an open and transcriptionally active genome. Taken together, these data suggest that histone in H. salinarum plays a minor role in DNA compaction but important roles in growth-phase-dependent gene expression and regulation of cell shape. Histone function in haloarchaea more closely resembles a regulator of gene expression than a chromatin-organizing protein like canonical eukaryotic histone. Histones comprise the major protein component of eukaryotic chromatin and are required for both genome packaging and global regulation of expression. The current paradigm maintains that archaea whose genes encode

Histones and their modifications in ovarian cancer - drivers of disease and therapeutic targets.

PubMed

Marsh, Deborah J; Shah, Jaynish S; Cole, Alexander J

2014-01-01

Epithelial ovarian cancer has the highest mortality of the gynecological malignancies. High grade serous epithelial ovarian cancer (SEOC) is the most common subtype, with the majority of women presenting with advanced disease where 5-year survival is around 25%. Platinum-based chemotherapy in combination with paclitaxel remains the most effective treatment despite platinum therapies being introduced almost 40 years ago. Advances in molecular medicine are underpinning new strategies for the treatment of cancer. Major advances have been made by international initiatives to sequence cancer genomes. For SEOC, with the exception of TP53 that is mutated in virtually 100% of these tumors, there is no other gene mutated at high frequency. There is extensive copy number variation, as well as changes in methylation patterns that will influence gene expression. To date, the role of histones and their post-translational modifications in ovarian cancer is a relatively understudied field. Post-translational histone modifications play major roles in gene expression as they direct the configuration of chromatin and so access by transcription factors. Histone modifications include methylation, acetylation, and monoubiquitination, with involvement of enzymes including histone methyltransferases, histone acetyltransferases/deacetylases, and ubiquitin ligases/deubiquitinases, respectively. Complexes such as the Polycomb repressive complex also play roles in the control of histone modifications and more recently roles for long non-coding RNA and microRNAs are emerging. Epigenomic-based therapies targeting histone modifications are being developed and offer new approaches for the treatment of ovarian cancer. Here, we discuss histone modifications and their aberrant regulation in malignancy and specifically in ovarian cancer. We review current and upcoming histone-based therapies that have the potential to inform and improve treatment strategies for women with ovarian cancer.

Factors affecting injury severity of vehicle occupants following road traffic collisions.

PubMed

Abu-Zidan, Fikri M; Eid, Hani O

2015-01-01

We aimed to define factors affecting injury severity of vehicle occupants following road traffic collisions (RTC). 422 vehicle occupants (343 males, 81.3%) with RTC-related injuries were prospectively studied over 18 months. General linear model was used to test the effect of age, gender, alcohol and drug use, time of injury, mechanism of injury, size and speed of the vehicle, position in the vehicle, seatbelt usage, and air bag deployment on the Injury Severity Score (ISS) of the vehicle occupants. The mean (range) age of patients was 28.2 (1-78) years and the mean (range) ISS was 7.9 (1-50). Front impact was the most common mechanism of injury (32.9%) followed by rollover (25.6%) and side impact (22.3%). 18.2% used seatbelts. The general linear model was highly significant and showed that mechanism of injury (p<0.0001), speed of the vehicle (p=0.02), and age of the vehicle occupant (p=0.03) significantly affected the Injury Severity Score. The mechanism of the RTC, the vehicle speed, and age of the vehicle occupant are the most important factors affecting the severity of road traffic collision injuries. A detailed history of the mechanism of injury is important for alerting clinicians to severity of injury, the need for admission, and workup of the patients. Furthermore, strict speed limit enforcement is an injury prevention priority in our community. Copyright © 2014 Elsevier Ltd. All rights reserved.

Factors associated with occupational strain among Chinese teachers: a cross-sectional study.

PubMed

Yang, X; Wang, L; Ge, C; Hu, B; Chi, T

2011-02-01

With the reform of the education system in China, teachers are suffering from more occupational strain, which is believed to impair their working state indirectly and affect their health. This study assessed occupational strain and explored the related factors among Chinese teachers. Cross-sectional with cluster sampling. The study population was composed of 3570 school teachers working in 64 primary and middle schools in Heping District in Shenyang, China. Data were collected using a self-administered questionnaire (the Chinese version of the Occupational Stress Inventory scale). Multivariate linear regression analyses were performed to study the factors related to occupational strain. The average score on the Personal Strain Questionnaire (PSQ) for the whole study population was 106.5 (107.5 in men and 106.3 in women). Teachers with chronic disease, a greater number of days of sick leave, recent experience of a stressful life event and divorced/separated/widowed status tended to suffer greater strain than their peers. Regression analyses showed that the PSQ score was significantly associated with role overload, role boundary, responsibility and physical environment, and inversely associated with recreation and rational coping. The most crucial predictors of occupational strain were chronic disease, days of sick leave, recent experience of a stressful life event and marital status. Being a class teacher was the strongest indicator of interpersonal strain. Self-care was associated with vocational strain and psychological strain, and inversely associated with physical strain. Most teachers in this study experienced a high degree of occupational strain. Chronic disease, days of sick leave, recent experience of a stressful life event and divorced/separated/widowed status played prominent roles in occupational strain. In addition, role overload, role boundary, responsibility and physical environment induce occupational strain, while recreation and rational coping have

Archaeal DNA on the histone merry-go-round.

PubMed

Bhattacharyya, Sudipta; Mattiroli, Francesca; Luger, Karolin

2018-05-04

How did the nucleosome, the fundamental building block of all eukaryotic chromatin, evolve? This central question has been impossible to address because the four core histones that make up the protein core of the nucleosome are so highly conserved in all eukaryotes. With the discovery of small, minimalist histone-like proteins in most known archaea, the likely origin of histones was identified. We recently determined the structure of an archaeal histone-DNA complex, revealing that archaeal DNA topology and protein-DNA interactions are astonishingly similar compared to the eukaryotic nucleosome. This was surprising since most archaeal histones form homodimers which consist only of the minimal histone fold and are devoid of histone tails and extensions. Unlike eukaryotic H2A-H2B and H3-H4 heterodimers that assemble into octameric particles wrapping ~150 bp DNA, archaeal histones form polymers around which DNA coils in a quasi-continuous superhelix. At any given point, this superhelix has the same geometry as nucleosomal DNA. This suggests that the architectural role of histones (i.e. the ability to bend DNA into a nucleosomal superhelix) was established before archaea and eukaryotes diverged, while the ability to form discrete particles, together with signaling functions of eukaryotic chromatin (i.e. epigenetic modifications) were secondary additions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Occupational Risk Factors and the Relationship of Smoking with Anxiety and Depression

PubMed Central

Ergün, Dilek; Ergan, Begüm; Kurt, Özlem Kar

2018-01-01

OBJECTIVES The aim of the present study was to evaluate the relation of smoking with anxiety and depression in workers who were exposed to occupational risk factors. For this purpose, working time, smoking status, nicotine dependence, and respiratory functions of the workers who were exposed to physical and/or chemical harmful substances were evaluated and the presence of anxiety/depression was investigated. MATERIAL AND METHODS Male workers who were exposed to occupational risk factors such as solvents, heavy metals, and dust and visited the outpatient clinic for occupational diseases within a one-year period were included. Pulmonary Function Test and Fagerström Test for Nicotine Dependence were performed. Anxiety and depression statuses of the workers were assessed using the Hospital Anxiety and Depression Scale. RESULTS The mean age of 665 male workers was 45 y (range, 38–48 y), and they were most commonly exposed to solvents (45.9%), followed by heavy metal fume/dust (20.9%). Of the workers, 252 (37.9%) had anxiety, 294 (44.2%) had depression, and 171 (25.7%) had both. More than half of the workers in each occupation/exposure group were smokers. Respiratory complaints were present in 34% of the workers. According to the regression analysis, the presence of respiratory system complaints was found to be a significant risk factor for anxiety, depression, and anxiety plus depression. CONCLUSION In conclusion, smoking and anxiety/depression were found to be the conditions affecting more than half of the workers with occupational exposure. PMID:29755811

Isolation and analysis of linker histones across cellular compartments

PubMed Central

Harshman, Sean W.; Chen, Michael M.; Branson, Owen E.; Jacob, Naduparambil K.; Johnson, Amy J.; Byrd, John C.; Freitas, Michael A.

2013-01-01

Analysis of histones, especially histone H1, is severely limited by immunological reagent availability. This paper describes the application of cellular fractionation with LC-MS for profiling histones in the cytosol and upon chromatin. First, we show that linker histones enriched by cellular fractionation gives less nuclear contamination and higher histone content than when prepared by nuclei isolation. Second, we profiled the soluble linker histones throughout the cell cycle revealing phosphorylation increases as cells reach mitosis. Finally, we monitored histone H1.2–H1.5 translocation to the cytosol in response to the CDK inhibitor flavopiridol in primary CLL cells treated ex vivo. Data shows all H1 variants translocate in response to drug treatment with no specific order to their cytosolic appearance. The results illustrate the utility of cellular fractionation in conjunction with LC-MS for the analysis of histone H1 throughout the cell. PMID:24013129

[Occupational stress in assembly line workers in electronics manufacturing service and related influencing factors].

PubMed

Ji, Y Q; Li, S; Wang, C; Wang, J; Liu, X M

2016-10-20

Objective: To investigate occupational stress in assembly line workers in electronics manu-facturing service (EMS) and related influencing factors. Methods: From June to October, 2015, a cross-sectional survey was performed for 5 944 assembly line workers in EMS (observation group) and 6 270 workers from other posts (non-assembly line workers and management personnel; control group) using the self-made questionnaire for basic information, job demand-control (JDC) model questionnaire, and effort-reward imbalance (ERI) model questionnaire to collect respondents' basic information and occupational stress. Results: The observation group had significantly lower work autonomy, social support, and work reward scores than the control group (2.72 ± 0.63/3.64 ± 0.68/4.06 ± 0.80 vs 3.00 ± 0.67/3.83 ± 0.68/4.24 ± 0.75, t =23.53, 15.41, and 12.70, all P <0.05) , as well as significantly higher work effort and job involvement scores than the control group (2.34±0.78/2.48±0.78 vs 2.21±0.80/2.33±0.77, t =-9.08 and-10.90, both P <0.05). The observation group had significantly higher proportions of workers with occupational stress determined by JDC and ERI models than the control group (64.5%/12.7% vs 52.6%/9.9%, χ 2 =182.26 and 23.41, both P <0.05). Female sex, migrant workers, working time >60 hours/week, and sleeping time <7 hours/day were major risk factors for occupational stress in JDC model; education background of Bachelor's degree or above, working time >60 hours/week, and sleeping time<7 hours/day were major risk factors for occupational stress in ERI model, while female sex and a high monthly income reduced the risk of occupational stress in ERI model. Conclusion: Assembly line workers in EMS are a relatively vulnerable group and have a high degree of occupational stress. Working time >60 hours/week and sleeping time <7 hours/day are major risk factors for occupational stress.

Histone acetyltransferase Enok regulates oocyte polarization by promoting expression of the actin nucleation factor spire.

PubMed

Huang, Fu; Paulson, Ariel; Dutta, Arnob; Venkatesh, Swaminathan; Smolle, Michaela; Abmayr, Susan M; Workman, Jerry L

2014-12-15

KAT6 histone acetyltransferases (HATs) are highly conserved in eukaryotes and have been shown to play important roles in transcriptional regulation. Here, we demonstrate that the Drosophila KAT6 Enok acetylates histone H3 Lys 23 (H3K23) in vitro and in vivo. Mutants lacking functional Enok exhibited defects in the localization of Oskar (Osk) to the posterior end of the oocyte, resulting in loss of germline formation and abdominal segments in the embryo. RNA sequencing (RNA-seq) analysis revealed that spire (spir) and maelstrom (mael), both required for the posterior localization of Osk in the oocyte, were down-regulated in enok mutants. Chromatin immunoprecipitation showed that Enok is localized to and acetylates H3K23 at the spir and mael genes. Furthermore, Gal4-driven expression of spir in the germline can largely rescue the defective Osk localization in enok mutant ovaries. Our results suggest that the Enok-mediated H3K23 acetylation (H3K23Ac) promotes the expression of spir, providing a specific mechanism linking oocyte polarization to histone modification. © 2014 Huang et al.; Published by Cold Spring Harbor Laboratory Press.

Histone modifications in the male germ line of Drosophila.

PubMed

Hennig, Wolfgang; Weyrich, Alexandra

2013-02-22

In the male germ line of Drosophila chromatin remains decondensed and highly transcribed during meiotic prophase until it is rapidly compacted. A large proportion of the cell cycle-regulated histone H3.1 is replaced by H3.3, a histone variant encoded outside the histone repeat cluster and not subject to cell cycle controlled expression. We investigated histone modification patterns in testes of D. melanogaster and D. hydei. In somatic cells of the testis envelope and in germ cells these modification patterns differ from those typically seen in eu- and heterochromatin of other somatic cells. During the meiotic prophase some modifications expected in active chromatin are not found or are found at low level. The absence of H4K16ac suggests that dosage compensation does not take place. Certain histone modifications correspond to either the cell cycle-regulated histone H3.1 or to the testis-specific variant H3.3. In spermatogonia we found H3K9 methylation in cytoplasmic histones, most likely corresponding to the H3.3 histone variant. Most histone modifications persist throughout the meiotic divisions. The majority of modifications persist until the early spermatid nuclei, and only a minority further persist until the final chromatin compaction stages before individualization of the spermatozoa. Histone modification patterns in the male germ line differ from expected patterns. They are consistent with an absence of dosage compensation of the X chromosome during the male meiotic prophase. The cell cycle-regulated histone variant H3.1 and H3.3, expressed throughout the cell cycle, also vary in their modification patterns. Postmeiotically, we observed a highly complex pattern of the histone modifications until late spermatid nuclear elongation stages. This may be in part due to postmeiotic transcription and in part to differential histone replacement during chromatin condensation.

Occupational Injuries in Germany: Population-Wide National Survey Data Emphasize the Importance of Work-Related Factors.

PubMed

Rommel, Alexander; Varnaccia, Gianni; Lahmann, Nils; Kottner, Jan; Kroll, Lars Eric

2016-01-01

Unintentional injuries cause much of the global mortality burden, with the workplace being a common accident setting. Even in high-income economies, occupational injury figures remain remarkably high. Because risk factors for occupational injuries are prone to confounding, the present research takes a comprehensive approach. To better understand the occurrence of occupational injuries, sociodemographic factors and work- and health-related factors are tested simultaneously. Thus, the present analysis aims to develop a comprehensive epidemiological model that facilitates the explanation of varying injury rates in the workplace. The representative phone survey German Health Update 2010 provides information on medically treated occupational injuries sustained in the year prior to the interview. Data were collected on sociodemographics, occupation, working conditions, health-related behaviors, and chronic diseases. For the economically active population (18-70 years, n = 14,041), the 12-month prevalence of occupational injuries was calculated with a 95% confidence interval (CI). Blockwise multiple logistic regression was applied to successively include different groups of variables. Overall, 2.8% (95% CI 2.4-3.2) of the gainfully employed population report at least one occupational injury (women: 0.9%; 95% CI 0.7-1.2; men: 4.3%; 95% CI 3.7-5.0). In the fully adjusted model, male gender (OR 3.16) and age 18-29 (OR 1.54), as well as agricultural (OR 5.40), technical (OR 3.41), skilled service (OR 4.24) or manual (OR 5.12), and unskilled service (OR 3.13) or manual (OR 4.97) occupations are associated with higher chances of occupational injuries. The same holds for frequent stressors such as heavy carrying (OR 1.78), working in awkward postures (OR 1.46), environmental stress (OR 1.48), and working under pressure (OR 1.41). Among health-related variables, physical inactivity (OR 1.47) and obesity (OR 1.73) present a significantly higher chance of occupational injuries

Epigenetic Control and Cancer: The Potential of Histone Demethylases as Therapeutic Targets

PubMed Central

Lizcano, Fernando; Garcia, Jeison

2012-01-01

The development of cancer involves an immense number of factors at the molecular level. These factors are associated principally with alterations in the epigenetic mechanisms that regulate gene expression profiles. Studying the effects of chromatin structure alterations, which are caused by the addition/removal of functional groups to specific histone residues, are of great interest as a promising way to identify markers for cancer diagnosis, classify the disease and determine its prognosis, and these markers could be potential targets for the treatment of this disease in its different forms. This manuscript presents the current point of view regarding members of the recently described family of proteins that exhibit histone demethylase activity; histone demethylases are genetic regulators that play a fundamental role in both the activation and repression of genes and whose expression has been observed to increase in many types of cancer. Some fundamental aspects of their association with the development of cancer and their relevance as potential targets for the development of new therapeutic strategies at the epigenetic level are discussed in the following manuscript. PMID:24280700

Emerging roles of lysine methylation on non-histone proteins.

PubMed

Zhang, Xi; Huang, Yaling; Shi, Xiaobing

2015-11-01

Lysine methylation is a common posttranslational modification (PTM) of histones that is important for the epigenetic regulation of transcription and chromatin in eukaryotes. Increasing evidence demonstrates that in addition to histones, lysine methylation also occurs on various non-histone proteins, especially transcription- and chromatin-regulating proteins. In this review, we will briefly describe the histone lysine methyltransferases (KMTs) that have a broad spectrum of non-histone substrates. We will use p53 and nuclear receptors, especially estrogen receptor alpha, as examples to discuss the dynamic nature of non-histone protein lysine methylation, the writers, erasers, and readers of these modifications, and the crosstalk between lysine methylation and other PTMs in regulating the functions of the modified proteins. Understanding the roles of lysine methylation in normal cells and during development will shed light on the complex biology of diseases associated with the dysregulation of lysine methylation on both histones and non-histone proteins.

Histone Hl-DNA interaction. Influence of phosphorylation on the interaction of histone Hl with linear fragmented DNA.

PubMed Central

Glotov, B O; Nikolaev, L G; Kurochkin, S N; Severin, E S

1977-01-01

By measuring the fluorescence polarization of fluorescent histone H1 derivatives complexed with DNA, binding of the histone to DNA was studied as a function of ionic strength in the solution prior to and after the H1 phosphorylation on Ser-37 residue. Fluorescent labels were covalently linked either specifically to Tyr-72 residues or unspecifically to lysine residues in the H1 polypeptide chain. The values of the corresponding rotational relaxation times showed that at low ionic strength all the segments of the H1 molecule were immobilized on binding to DNA. The gradual increasing NaC1 concentration in the solution of H1-DNA complex was accompanied at first by additional retardation of the histone mobility in the complex, and then by progressive release of histone H1 from from the complex which was completed at 0.5-0.6 M NaC1 irrespective of phosphorylation. tat the same time the phosphorylation of histone H1 led to removal of the central and, presumably, N-terminal regions of H1 from DNA. PMID:194228

An epidemiologic study of occupational stress factors in Mumbai police personnel.

PubMed

Almale, Balaji D; Vankudre, Ashok J; Bansode-Gokhe, Seema S; Pawar, Vrushali K

2014-01-01

Occupational stress is common to each and every organization at various levels of hierarchy. The police organization is no exception to this. Rather policing is widely recognized as more stressful than any other occupation, nature of work, irregular duty hours, and many more factors, which can trigger stress. The present study was done to highlight some of these stressful factors in Mumbai police. Simple as well as systematic random sampling technique was adopted to get equal representation from each zone as well as region from Mumbai police. Occupational stress index (OSI) questionnaire was prepared, pilot tested, and validated for screening stress. We screened 276 policemen for occupational stress. Seventy-three percent of them were in the 30-50 years age group, and most of them (49%) studied up to H.S.C. Ninety-one percent were married and 56% had reported duty hours 12-16 h/day. Seventy-one percent were addicted to any of the substance. After screening we found 73% moderately stressed, whereas 18% highly stressed policemen. Sociodemographic factors which were age group (50-58 years), duration of service in years (>25 years), duration of duty hours (>16 h/day), addiction habits, and number of monthly holidays (no holiday). We found role ambiguity, under participation, role overload, strenuous working condition, and unprofitability as predominant scales in OSI. So prevention as well as management of stress in policemen is the necessity of the current situation. This stress can be managed at organizational level by adopting right techniques, whereas at individual level by habituating right behavior and attitude.

Epigenetic Repression of Matrix Metalloproteinases in Myofibroblastic Hepatic Stellate Cells through Histone Deacetylases 4

PubMed Central

Qin, Lan; Han, Yuan-Ping

2010-01-01

Matrix metalloproteinases (MMPs), which are highly expressed in acute injury, are progressively repressed or silenced in fibrotic liver, favoring extracellular matrix accumulation, while the underlying mechanism is largely unknown. Similarly, normal/quiescent hepatic stellate cells (HSCs) express high levels of MMPs in response to injury signals, such as interleukin-1. After transdifferentiation, the myofibroblastic HSCs are incapable of expressing many MMPs; however, the major signaling pathways required for MMP expression are intact, indicating that repression is at the level of the chromatin. Indeed, both the MMP9 and MMP13 genes are inaccessible to transcription factors and RNA polymerase II, in association with impaired histone acetylation in their promoters. In accordance with impaired histone acetylation at the cellular level, histone deacetylase-4 is accumulated during HSC transdifferentiation. Furthermore, ectopic expression of histone deacetylase-4 in quiescent HSCs results in repression of MMP promoter activities as well as endogenous MMP9 protein expression. Thus, our findings suggest that a histone deacetylase-4-dependent mechanism underlies the epigenetic silencing of MMP genes during tissue fibrogenesis. PMID:20847282

DNA-mediated association of two histone-bound complexes of yeast Chromatin Assembly Factor-1 (CAF-1) drives tetrasome assembly in the wake of DNA replication.

PubMed

Mattiroli, Francesca; Gu, Yajie; Yadav, Tejas; Balsbaugh, Jeremy L; Harris, Michael R; Findlay, Eileen S; Liu, Yang; Radebaugh, Catherine A; Stargell, Laurie A; Ahn, Natalie G; Whitehouse, Iestyn; Luger, Karolin

2017-03-18

Nucleosome assembly in the wake of DNA replication is a key process that regulates cell identity and survival. Chromatin assembly factor 1 (CAF-1) is a H3-H4 histone chaperone that associates with the replisome and orchestrates chromatin assembly following DNA synthesis. Little is known about the mechanism and structure of this key complex. Here we investigate the CAF-1•H3-H4 binding mode and the mechanism of nucleosome assembly. We show that yeast CAF-1 binding to a H3-H4 dimer activates the Cac1 winged helix domain interaction with DNA. This drives the formation of a transient CAF-1•histone•DNA intermediate containing two CAF-1 complexes, each associated with one H3-H4 dimer. Here, the (H3-H4) 2 tetramer is formed and deposited onto DNA. Our work elucidates the molecular mechanism for histone deposition by CAF-1, a reaction that has remained elusive for other histone chaperones, and it advances our understanding of how nucleosomes and their epigenetic information are maintained through DNA replication.

The Histone Chaperone NRP1 Interacts with WEREWOLF to Activate GLABRA2 in Arabidopsis Root Hair Development

PubMed Central

Rong, Liang; Luo, Qiang; Wang, Baihui; Zhou, Nana; Zhang, Chi; Feng, Haiyang

2017-01-01

NUCLEOSOME ASSEMBLY PROTEIN1 (NAP1) defines an evolutionarily conserved family of histone chaperones and loss of function of the Arabidopsis thaliana NAP1 family genes NAP1-RELATED PROTEIN1 (NRP1) and NRP2 causes abnormal root hair formation. Yet, the underlying molecular mechanisms remain unclear. Here, we show that NRP1 interacts with the transcription factor WEREWOLF (WER) in vitro and in vivo and enriches at the GLABRA2 (GL2) promoter in a WER-dependent manner. Crystallographic analysis indicates that NRP1 forms a dimer via its N-terminal α-helix. Mutants of NRP1 that either disrupt the α-helix dimerization or remove the C-terminal acidic tail, impair its binding to histones and WER and concomitantly lead to failure to activate GL2 transcription and to rescue the nrp1-1 nrp2-1 mutant phenotype. Our results further demonstrate that WER-dependent enrichment of NRP1 at the GL2 promoter is involved in local histone eviction and nucleosome loss in vivo. Biochemical competition assays imply that the association between NRP1 and histones may counteract the inhibitory effect of histones on the WER-DNA interaction. Collectively, our study provides important insight into the molecular mechanisms by which histone chaperones are recruited to target chromatin via interaction with a gene-specific transcription factor to moderate chromatin structure for proper root hair development. PMID:28138017

Silencing of IFN-stimulated gene transcription is regulated by histone H1 and its chaperone TAF-I.

PubMed

Kadota, Shinichi; Nagata, Kyosuke

2014-07-01

Chromatin structure and its alteration play critical roles in the regulation of transcription. However, the transcriptional silencing mechanism with regard to the chromatin structure at an unstimulated state of the interferon (IFN)-stimulated gene (ISG) remains unclear. Here we investigated the role of template activating factor-I (TAF-I, also known as SET) in ISG transcription. Knockdown (KD) of TAF-I increased ISG transcript and simultaneously reduced the histone H1 level on the ISG promoters during the early stages of transcription after IFN stimulation from the unstimulated state. The transcription factor levels on the ISG promoters were increased in TAF-I KD cells only during the early stages of transcription. Furthermore, histone H1 KD also increased ISG transcript. TAF-I and histone H1 double KD did not show the additive effect in ISG transcription, suggesting that TAF-I and histone H1 may act on the same regulatory pathway to control ISG transcription. In addition, TAF-I KD and histone H1 KD affected the chromatin structure near the ISG promoters. On the basis of these findings, we propose that TAF-I and its target histone H1 are key regulators of the chromatin structure at the ISG promoter to maintain the silent state of ISG transcription. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Organisational Factors of Occupational Accidents with Movement Disturbance (OAMD) and Prevention

PubMed Central

LECLERCQ, Sylvie

2014-01-01

Workplace design and upkeep, or human factors, are frequently advanced for explaining so-called Occupational Slip, Trip and Fall Accidents (OSTFAs). Despite scientific progress, these accidents, and more broadly Occupational Accidents with Movement Disturbance (OAMDs), are also commonly considered to be “simple”. This paper aims to stimulate changes in such perceptions by focusing on organisational factors that often combine with other accident factors to cause movement disturbance and injury in work situations. These factors frequently lead to arbitration between production and safety, which involves implementation of controls by workers. These controls can lead to greater worker exposure to OAMD risk. We propose a model that focuses on such controls to account specifically for the need to confront production and safety logics within a company and to enhance the potential for appropriate prevention action. These are then integrated into the set of controls highlighted by work organisation model developed by the NIOSH. PMID:25345425

Flexible histone tails in a new mesoscopic oligonucleosome model.

PubMed

Arya, Gaurav; Zhang, Qing; Schlick, Tamar

2006-07-01

We describe a new mesoscopic model of oligonucleosomes that incorporates flexible histone tails. The nucleosome cores are modeled using the discrete surface-charge optimization model, which treats the nucleosome as an electrostatic surface represented by hundreds of point charges; the linker DNAs are treated using a discrete elastic chain model; and the histone tails are modeled using a bead/chain hydrodynamic approach as chains of connected beads where each bead represents five protein residues. Appropriate charges and force fields are assigned to each histone chain so as to reproduce the electrostatic potential, structure, and dynamics of the corresponding atomistic histone tails at different salt conditions. The dynamics of resulting oligonucleosomes at different sizes and varying salt concentrations are simulated by Brownian dynamics with complete hydrodynamic interactions. The analyses demonstrate that the new mesoscopic model reproduces experimental results better than its predecessors, which modeled histone tails as rigid entities. In particular, our model with flexible histone tails: correctly accounts for salt-dependent conformational changes in the histone tails; yields the experimentally obtained values of histone-tail mediated core/core attraction energies; and considers the partial shielding of electrostatic repulsion between DNA linkers as a result of the spatial distribution of histone tails. These effects are crucial for regulating chromatin structure but are absent or improperly treated in models with rigid histone tails. The development of this model of oligonucleosomes thus opens new avenues for studying the role of histone tails and their variants in mediating gene expression through modulation of chromatin structure.

The Role of Histone Tails in the Nucleosome: A Computational Study

PubMed Central

Erler, Jochen; Zhang, Ruihan; Petridis, Loukas; Cheng, Xiaolin; Smith, Jeremy C.; Langowski, Jörg

2014-01-01

Histone tails play an important role in gene transcription and expression. We present here a systematic computational study of the role of histone tails in the nucleosome, using replica exchange molecular dynamics simulations with an implicit solvent model and different well-established force fields. We performed simulations for all four histone tails, H4, H3, H2A, and H2B, isolated and with inclusion of the nucleosome. The results confirm predictions of previous theoretical studies for the secondary structure of the isolated tails but show a strong dependence on the force field used. In the presence of the entire nucleosome for all force fields, the secondary structure of the histone tails is destabilized. Specific contacts are found between charged lysine and arginine residues and DNA phosphate groups and other binding sites in the minor and major DNA grooves. Using cluster analysis, we found a single dominant configuration of binding to DNA for the H4 and H2A histone tails, whereas H3 and H2B show multiple binding configurations with an equal probability. The leading stabilizing contribution for those binding configurations is the attractive interaction between the positively charged lysine and arginine residues and the negatively charged phosphate groups, and thus the resulting charge neutralization. Finally, we present results of molecular dynamics simulations in explicit solvent to confirm our conclusions. Results from both implicit and explicit solvent models show that large portions of the histone tails are not bound to DNA, supporting the complex role of these tails in gene transcription and expression and making them possible candidates for binding sites of transcription factors, enzymes, and other proteins. PMID:25517156

Potential non-oncological applications of histone deacetylase inhibitors.

PubMed

Ververis, Katherine; Karagiannis, Tom C

2011-01-01

Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutic drugs. Their clinical utility in oncology stems from their intrinsic cytotoxic properties and combinatorial effects with other conventional cancer therapies. To date, the histone deacetylase inhibitors suberoylanilide hydroxamic acid (Vorinostat, Zolinza®) and depsipeptide (Romidepsin, Istodax®) have been approved by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Further, there are currently over 100 clinical trials involving the use of histone deacetylase inhibitors in a wide range of solid and hematological malignancies. The therapeutic potential of histone deacetylase inhibitors has also been investigated for numerous other diseases. For example, the cytotoxic properties of histone deacetylase inhibitors are currently being harnessed as a potential treatment for malaria, whereas the efficacy of these compounds for HIV relies on de-silencing latent virus. The anti-inflammatory properties of histone deacetylase inhibitors are the predominant mechanisms for other diseases, such as hepatitis, systemic lupus erythematosus and a wide range of neurodegenerative conditions. Additionally, histone deacetylase inhibitors have been shown to be efficacious in animal models of cardiac hypertrophy and asthma. Broad-spectrum histone deacetylase inhibitors are clinically available and have been used almost exclusively in preclinical systems to date. However, it is emerging that class- or isoform-specific compounds, which are becoming more readily available, may be more efficacious particularly for non-oncological applications. The aim of this review is to provide an overview of the effects and clinical potential of histone deacetylase inhibitors in various diseases. Apart from applications in oncology, the discussion is focused on the potential efficacy of histone deacetylase inhibitors for the treatment of neurodegenerative diseases, cardiac

Potential non-oncological applications of histone deacetylase inhibitors

PubMed Central

Ververis, Katherine; Karagiannis, Tom C

2011-01-01

Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutic drugs. Their clinical utility in oncology stems from their intrinsic cytotoxic properties and combinatorial effects with other conventional cancer therapies. To date, the histone deacetylase inhibitors suberoylanilide hydroxamic acid (Vorinostat, Zolinza®) and depsipeptide (Romidepsin, Istodax®) have been approved by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Further, there are currently over 100 clinical trials involving the use of histone deacetylase inhibitors in a wide range of solid and hematological malignancies. The therapeutic potential of histone deacetylase inhibitors has also been investigated for numerous other diseases. For example, the cytotoxic properties of histone deacetylase inhibitors are currently being harnessed as a potential treatment for malaria, whereas the efficacy of these compounds for HIV relies on de-silencing latent virus. The anti-inflammatory properties of histone deacetylase inhibitors are the predominant mechanisms for other diseases, such as hepatitis, systemic lupus erythematosus and a wide range of neurodegenerative conditions. Additionally, histone deacetylase inhibitors have been shown to be efficacious in animal models of cardiac hypertrophy and asthma. Broad-spectrum histone deacetylase inhibitors are clinically available and have been used almost exclusively in preclinical systems to date. However, it is emerging that class- or isoform-specific compounds, which are becoming more readily available, may be more efficacious particularly for non-oncological applications. The aim of this review is to provide an overview of the effects and clinical potential of histone deacetylase inhibitors in various diseases. Apart from applications in oncology, the discussion is focused on the potential efficacy of histone deacetylase inhibitors for the treatment of neurodegenerative diseases, cardiac

Cancer Chemoprotection Through Nutrient-mediated Histone Modifications

PubMed Central

Gao, Yifeng; Tollefsbol, Trygve O.

2016-01-01

Epigenetics, the study of heritable changes in gene expression without modifying the nucleotide sequence, is among the most important topics in medicinal chemistry and cancer chemoprotection. Among those changes, DNA methylation and histone modification have been shown to be associated with various types of cancers in a number of ways, many of which are regulated by dietary components that are mostly found in plants. Although, mechanisms of nutrient components affecting histone acetylation/deacetylation in cancer are widely studied, how those natural compounds affect cancer through other histone modifications, such as methylation, phosphorylation and ubiquitylation, is rarely reviewed. Thus, this review article discusses impacts recently studied on histone acetylation as well as other histone modifications by dietary components, such as genistein, resveratrol, curcumin, epigallocatechin-3-gallate (EGCG), 3,3′-diindolylmethane (DIM), diallyl disulfide, garcinol, procyanidin B3, quercetin, sulforaphane and other isothiocyanates, in various types of cancer. PMID:25891109

Occupational and environmental risk factors for chronic rhinosinusitis in China: a multicentre cross-sectional study.

PubMed

Gao, Wen-Xiang; Ou, Chun-Quan; Fang, Shu-Bin; Sun, Yue-Qi; Zhang, Hua; Cheng, Lei; Wang, Yan-Jun; Zhu, Dong-Dong; Lv, Wei; Liu, Shi-Xi; Li, P Z; Xu, Geng; Shi, Jianbo; Fu, Qing-Ling

2016-05-17

Chronic rhinosinusitis (CRS) is defined as a condition of inflammation in the paranasal sinus mucosa persisting for more than 12 weeks. We previously reported that the prevalence of CRS was about 8 % in China. Here, we aim to investigate the occupational and environmental risk factors associated with CRS. Data were collected from seven Chinese cities: Urumqi, Changchun, Beijing, Wuhan, Chengdu, Huaian and Guangzhou. CRS was diagnosed according to the European Position Paper on Rhinosinusitis and Nasal Polyps (EP(3)OS) document. Participants were asked to complete a standardized questionnaire, which was developed by the Global Allergy and Asthma European Network (GA(2)LEN) project and covered sociodemographic characteristics, CRS-related symptoms and occupational and environmental exposures. We evaluated the association between CRS and various occupational and environmental factors using odds ratios (ORs) and 95 % confidence intervals (95 % CIs). The total study population consisted of 10,633 subjects, 850 (7.99 %) of whom were defined as having CRS according to the EP(3)OS criteria. We found that there were significant associations between occupational and environmental factors and CRS. Specifically, having a clearance-related job, occupational exposure to dust, occupational exposure to poisonous gas, a pet at home or carpet at home or at the workplace were risk factors for CRS. Additionally, the method used to keep warm in winter, the duration of time spent using air conditioning in summer and the frequency of exposure to mouldy or damp environments were significantly different in subjects with and without CRS. Our data showed that some occupational and environmental exposures are strongly associated with CRS, which aids in understanding the epidemiology of CRS.

Successful collaboration between occupational health service providers and client companies: Key factors.

PubMed

Schmidt, Lisa; Sjöström, John; Antonsson, Ann-Beth

2015-06-05

Occupational health services (OHS) are often described as an important resource to reduce work-related diseases and improve the workplace. This paper identifies key factors for successful collaboration between Swedish OHS providers and their client companies. Interviews were carried out with representatives of 15 companies and their OHS providers. The interviews were transcribed and their content analyzed. The results revealed that successful collaboration was highly correlated with six factors. First, the collaboration depends on both parties; ``it takes two to tango''. Second, the company and the OHS provider have a joint commitment to a long-term collaboration. Third, the collaboration is built on frequent contact at different organizational levels. Fourth, the company has a well-structured work environment for occupational health and safety management. Fifth, the OHS provider uses a consultative approach in its prevention and promotion activities. Finally, OHS providers seek to treat the company, not the individual. Our research indicates that a successful collaboration requires both occupational health and safety management (OHSM) within the company and the assistance of a competent OHS provider. A change toward more promotion and prevention services benefits the company, since the occupational health services are better tailored to the company's needs.

[The Effect of Social-Psychological Factors on the Development of Occupational Stress].

PubMed

Kalinina, S A; Yushkova, O I

2015-01-01

The article presents data on social-psychological factors which cause the occupational stress. The results showed that there is a link between the level of work motivation and the physiological cost of work. We observed a number of peculiarities of occupational stress development caused by psychoemotional tension depending on the class of intensity of intellectual labor; we also studied biological age of the subjects. The speed of ageing of the employees who work under conditions of emotional stress (direct or indirect responsibility for the safety of other people) was found to increase. The study suggested promising directions of occupational stress prevention.

Risk factors for developing jumper's knee in sport and occupation: a review

PubMed Central

Tiemessen, Ivo JH; Kuijer, P Paul FM; Hulshof, Carel TJ; Frings-Dresen, Monique HW

2009-01-01

Background The onset of jumper's knee is generally associated with sports and sporting activities. Employees in certain professions might be at risk as well for developing jumper's knee. Therefore, it is of interest to identify risk factors in sport and/or occupation. Findings A systematic search of the international scientific literature was performed until November 2008 in the scientific databases (a) Medline, (b) Embase, and (c) SportDiscus. All types of studies were included. The search strategy retrieved ten articles about risk factors in sport that met the inclusion criteria. Risk factors that could be identified are; playing volleyball (4 studies), playing basketball (3 studies), training and playing volleyball/basketball more than 12 hours per week (2 studies), in combination with weight-bearing activities of at least 5 hours per week (1 study) and playing or training on a hard surface (1 study). No studies were found regarding occupation that fulfilled the inclusion criteria. Conclusion Playing volleyball and basketball has a positive association with the onset or worsening of jumper's knee. Other risk factors are training and playing hours of at least 12 hours per week and/or in combination with weight training of at least 5 hours per week, and/or with playing or training on a hard surface. We did not find a specific occupational risk factor. PMID:19586529

Association between socio-demographic, psychosocial, material and occupational factors and self-reported health among workers in Europe.

PubMed

Schütte, Stefanie; Chastang, Jean-François; Parent-Thirion, Agnès; Vermeylen, Greet; Niedhammer, Isabelle

2014-06-01

The aim of this study was to explore the associations between socio-demographic, psychosocial, material and occupational factors and self-reported health (SRH) in the European working population. Another objective was to examine whether these associations varied according to occupation and country. This study was based on data from the European quality of life survey 2007 including 17,005 workers from 31 European countries. SRH was measured using a single item. Factors were classified into four different groups: socio-demographic, psychosocial, material and occupational factors. The associations between these factors and SRH were examined using multilevel logistic regression analyses including interaction tests. When all four groups of factors were studied together, age, occupation, urbanization level, origin, trust level, social exclusion, material deprivation, financial and neighbourhood problems, access to medical services, quality of public services, psychological job demands, job reward, work-life imbalance and dangerous/unhealthy working conditions were associated with poor SRH. Almost no differences were found in these associations according to occupation and country. Various factors were associated with poor SRH. This study gave a first European overview of the associations between socio-demographic, psychosocial, material and occupational factors and SRH in Europe and could provide better advice to policy-makers at a European level. © The Author 2013. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Antibodies to H1 histone from the sera of HIV-infected patients recognize and catalyze site-specific degradation of this histone.

PubMed

Baranova, Svetlana V; Dmitrienok, Pavel S; Ivanisenko, Nikita V; Buneva, Valentina N; Nevinsky, Georgy A

2017-03-01

Histones and their posttranslational modifications have key roles in chromatin remodeling and gene transcription. Besides intranuclear functions, histones act as damage-associated molecules when they are released into the extracellular space. Administration of histones to animals leads to systemic inflammatory and toxic responses. Autoantibodies with enzymatic activities (abzymes) are distinctive feature of some autoimmune and viral diseases. Electrophoretically and immunologically homogeneous IgGs containing no canonical enzymes were isolated from sera of human immunodeficiency virus-infected patients by chromatography on several affinity sorbents. In contrast to canonical proteases (trypsin, chymotrypsin, and proteinase K), IgGs from human immunodeficiency virus-infected patients purified by affinity chromatography on Sepharose containing immobilized histones specifically recognized and hydrolyzed only histones but not many other tested globular proteins. Using matrix-assisted laser desorption/ionization mass spectrometry, the sites of H1 histone (193 amino acids [AAs]) cleavage by anti-H1 histone IgGs were determined for the first time. It was shown that 1 cluster of 2 major and 4 moderate sites of cleavage is located at the beginning (106-112 AAs) of the known antigenic determinants disposed at the long C-terminal sequence of H1. Two clusters of minor and very weak sites of the protein cleavage correspond to middle (8 sites, 138-158 AAs) and terminal (5 sites, 166-176 AAs) parts of the antigenic determinants. It was shown that in contrast to canonical proteases, N-terminal part of H1 histone (1-136 AAs) containing no antigenic determinants is an unpredictably very resistant against hydrolysis by abzymes, while it can be easily cleavage by canonical proteases. Because histones act as damage-associated molecules, abzymes against H1 and other histones can play important role in pathogenesis of acquired immune deficiency syndrome and probably other different

SINE transcription by RNA polymerase III is suppressed by histone methylation but not by DNA methylation

PubMed Central

Varshney, Dhaval; Vavrova-Anderson, Jana; Oler, Andrew J.; Cowling, Victoria H.; Cairns, Bradley R.; White, Robert J.

2015-01-01

Short interspersed nuclear elements (SINEs), such as Alu, spread by retrotransposition, which requires their transcripts to be copied into DNA and then inserted into new chromosomal sites. This can lead to genetic damage through insertional mutagenesis and chromosomal rearrangements between non-allelic SINEs at distinct loci. SINE DNA is heavily methylated and this was thought to suppress its accessibility and transcription, thereby protecting against retrotransposition. Here we provide several lines of evidence that methylated SINE DNA is occupied by RNA polymerase III, including the use of high-throughput bisulphite sequencing of ChIP DNA. We find that loss of DNA methylation has little effect on accessibility of SINEs to transcription machinery or their expression in vivo. In contrast, a histone methyltransferase inhibitor selectively promotes SINE expression and occupancy by RNA polymerase III. The data suggest that methylation of histones rather than DNA plays a dominant role in suppressing SINE transcription. PMID:25798578

Occupational risk factors have to be considered in the definition of high-risk lung cancer populations.

PubMed

Wild, P; Gonzalez, M; Bourgkard, E; Courouble, N; Clément-Duchêne, C; Martinet, Y; Févotte, J; Paris, C

2012-03-27

The aim of this study was to compute attributable fractions (AF) to occupational factors in an area in North-Eastern France with high lung cancer rates and a past of mining and steel industry. A population-based case-control study among males aged 40-79 was conducted, including confirmed primary lung cancer cases from all hospitals of the study region. Controls were stratified by broad age-classes, district and socioeconomic classes. Detailed occupational and personal risk factors were obtained in face-to-face interviews. Cumulative occupational exposure indices were obtained from the questionnaires. Attributable fractions were computed from multiple unconditional logistic regression models. A total of 246 cases and 531 controls were included. The odds ratios (ORs) adjusted on cumulative smoking and family history of lung cancer increased significantly with the cumulative exposure indices to asbestos, polycyclic aromatic hydrocarbons and crystalline silica, and with exposure to diesel motor exhaust. The AF for occupational factors exceeded 50%, the most important contributor being crystalline silica and asbestos. These AFs are higher than most published figures. This can be because of the highly industrialised area or methods for exposure assessments. Occupational factors are important risk factors and should not be forgotten when defining high-risk lung cancer populations.

Occupational Injuries in Germany: Population-Wide National Survey Data Emphasize the Importance of Work-Related Factors

PubMed Central

Rommel, Alexander; Varnaccia, Gianni; Lahmann, Nils; Kottner, Jan; Kroll, Lars Eric

2016-01-01

Unintentional injuries cause much of the global mortality burden, with the workplace being a common accident setting. Even in high-income economies, occupational injury figures remain remarkably high. Because risk factors for occupational injuries are prone to confounding, the present research takes a comprehensive approach. To better understand the occurrence of occupational injuries, sociodemographic factors and work- and health-related factors are tested simultaneously. Thus, the present analysis aims to develop a comprehensive epidemiological model that facilitates the explanation of varying injury rates in the workplace. The representative phone survey German Health Update 2010 provides information on medically treated occupational injuries sustained in the year prior to the interview. Data were collected on sociodemographics, occupation, working conditions, health-related behaviors, and chronic diseases. For the economically active population (18–70 years, n = 14,041), the 12-month prevalence of occupational injuries was calculated with a 95% confidence interval (CI). Blockwise multiple logistic regression was applied to successively include different groups of variables. Overall, 2.8% (95% CI 2.4–3.2) of the gainfully employed population report at least one occupational injury (women: 0.9%; 95% CI 0.7–1.2; men: 4.3%; 95% CI 3.7–5.0). In the fully adjusted model, male gender (OR 3.16) and age 18–29 (OR 1.54), as well as agricultural (OR 5.40), technical (OR 3.41), skilled service (OR 4.24) or manual (OR 5.12), and unskilled service (OR 3.13) or manual (OR 4.97) occupations are associated with higher chances of occupational injuries. The same holds for frequent stressors such as heavy carrying (OR 1.78), working in awkward postures (OR 1.46), environmental stress (OR 1.48), and working under pressure (OR 1.41). Among health-related variables, physical inactivity (OR 1.47) and obesity (OR 1.73) present a significantly higher chance of occupational

An epidemiologic study of occupational stress factors in Mumbai police personnel

PubMed Central

Almale, Balaji D; Vankudre, Ashok J.; Bansode-Gokhe, Seema S.; Pawar, Vrushali K.

2014-01-01

Introduction: Occupational stress is common to each and every organization at various levels of hierarchy. The police organization is no exception to this. Rather policing is widely recognized as more stressful than any other occupation, nature of work, irregular duty hours, and many more factors, which can trigger stress. The present study was done to highlight some of these stressful factors in Mumbai police. Materials and Methods: Simple as well as systematic random sampling technique was adopted to get equal representation from each zone as well as region from Mumbai police. Occupational stress index (OSI) questionnaire was prepared, pilot tested, and validated for screening stress. Result: We screened 276 policemen for occupational stress. Seventy-three percent of them were in the 30–50 years age group, and most of them (49%) studied up to H.S.C. Ninety-one percent were married and 56% had reported duty hours 12–16 h/day. Seventy-one percent were addicted to any of the substance. After screening we found 73% moderately stressed, whereas 18% highly stressed policemen. Sociodemographic factors which were age group (50–58 years), duration of service in years (>25 years), duration of duty hours (>16 h/day), addiction habits, and number of monthly holidays (no holiday). We found role ambiguity, under participation, role overload, strenuous working condition, and unprofitability as predominant scales in OSI. So prevention as well as management of stress in policemen is the necessity of the current situation. This stress can be managed at organizational level by adopting right techniques, whereas at individual level by habituating right behavior and attitude. PMID:25598614

Occupational dermatitis in hairdressers - influence of individual and environmental factors.

PubMed

Carøe, Tanja K; Ebbehøj, Niels E; Agner, Tove

2017-03-01

Hairdressers are at risk of developing occupational contact dermatitis because of their intense contact with wet work in combination with chemicals. To perform an analysis of a cohort study of hairdressers with occupational contact dermatitis recognized in the period 2006-2011, focusing on individual and environmental factors associated with the disease. The study was a descriptive, register-based survey including all hairdressers with recognized occupational contact dermatitis in Denmark in the period January 2006 to September 2011. Data were obtained from the Danish National Board of Industrial Injuries. The study comprised 381 patients (373 women and 8 men). The median age was 25 years, 64.8% were apprentices, and 35.2% were fully trained hairdressers. The prevalence of atopic dermatitis was 36.0%, and was significantly higher among apprentices than among fully trained hairdressers (44.9% and 19.4%, respectively) (p < 0.001). Of the patients, 48.3% had their dermatitis recognized as occupational irritant contact dermatitis, 46.7% had their dermatitis recognized as as occupational allergic contact dermatitis or combined allergic and irritant contact dermatitis, and 5.0% were recognized as having occupational contact urticaria. The low median age, the high percentages of atopic dermatitis in apprentices and the fact that more apprentices than fully trained hairdressers had recognized occupational contact dermatitis underlines the importance of early prevention. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

FLASH is essential during early embryogenesis and cooperates with p73 to regulate histone gene transcription.

PubMed

De Cola, A; Bongiorno-Borbone, L; Bianchi, E; Barcaroli, D; Carletti, E; Knight, R A; Di Ilio, C; Melino, G; Sette, C; De Laurenzi, V

2012-02-02

Replication-dependent histone gene expression is a fundamental process occurring in S-phase under the control of the cyclin-E/CDK2 complex. This process is regulated by a number of proteins, including Flice-Associated Huge Protein (FLASH) (CASP8AP2), concentrated in specific nuclear organelles known as HLBs. FLASH regulates both histone gene transcription and mRNA maturation, and its downregulation in vitro results in the depletion of the histone pull and cell-cycle arrest in S-phase. Here we show that the transcription factor p73 binds to FLASH and is part of the complex that regulates histone gene transcription. Moreover, we created a novel gene trap to disrupt FLASH in mice, and we show that homozygous deletion of FLASH results in early embryonic lethality, owing to arrest of FLASH(-/-) embryos at the morula stage. These results indicate that FLASH is an essential, non-redundant regulator of histone transcription and cell cycle during embryogenesis.

Occupational exposure to organic solvents: a risk factor for pulmonary veno-occlusive disease.

PubMed

Montani, David; Lau, Edmund M; Descatha, Alexis; Jaïs, Xavier; Savale, Laurent; Andujar, Pascal; Bensefa-Colas, Lynda; Girerd, Barbara; Zendah, Inès; Le Pavec, Jerome; Seferian, Andrei; Perros, Frédéric; Dorfmüller, Peter; Fadel, Elie; Soubrier, Florent; Sitbon, Oliver; Simonneau, Gérald; Humbert, Marc

2015-12-01

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension characterised by predominant remodelling of pulmonary venules. Bi-allelic mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene were recently described as the major cause of heritable PVOD, but risk factors associated with PVOD remain poorly understood. Occupational exposures have been proposed as a potential risk factor for PVOD, but epidemiological studies are lacking.A case-control study was conducted in consecutive PVOD (cases, n=33) and pulmonary arterial hypertension patients (controls, n=65). Occupational exposure was evaluated via questionnaire interview with blinded assessments using an expert consensus approach and a job exposure matrix (JEM).Using the expert consensus approach, PVOD was significantly associated with occupational exposure to organic solvents (adjusted OR 12.8, 95% CI 2.7-60.8), with trichloroethylene being the main agent implicated (adjusted OR 8.2, 95% CI 1.4-49.4). JEM analysis independently confirmed the association between PVOD and trichloroethylene exposure. Absence of significant trichloroethylene exposure was associated with a younger age of disease (54.8±21.4 years, p=0.037) and a high prevalence of harbouring bi-allelic EIF2AK4 mutations (41.7% versus 0%, p=0.015).Occupational exposure to organic solvents may represent a novel risk factor for PVOD. Genetic background and environmental exposure appear to influence the phenotypic expression of the disease. Copyright ©ERS 2015.

Histone methylation and aging: Lessons learned from model systems

PubMed Central

McCauley, Brenna S.; Dang, Weiwei

2014-01-01

Aging induces myriad cellular and, ultimately, physiological changes that cause a decline in an organism's functional capabilities. Although the aging process and pathways that regulate it have been extensively studied, only in the last decade have we begun to appreciate that dynamic histone methylation may contribute to this process. In this review, we discuss recent work implicating histone methylation in aging. Loss of certain histone methyltransferases and demethylases changes lifespan in invertebrates, and alterations in histone methylation in aged organisms regulate lifespan and aging phenotypes, including oxidative stress-induced hormesis in yeast, insulin signaling in Caenorhabiditis elegans and mammals, and the senescence-associated secretory phenotype in mammals. In all cases where histone methylation has been shown to impact aging and aging phenotypes, it does so by regulating transcription, suggesting that this is a major mechanism of its action in this context. Histone methylation additionally regulates or is regulated by other cellular pathways that contribute to or combat aging. Given the numerous processes that regulate aging and histone methylation, and are in turn regulated by them, the role of histone methylation in aging is almost certainly underappreciated. PMID:24859460

[Stress as an occupational risk factor among policemen of road patrol service].

PubMed

Fedotova, I V; Chernikova, E F

The hygienic evaluation of occupational factors which characterized working conditions of traffic policemen of road patrol service was performed. The authors found that along with high neuro-emotional occupational stress in traffic policemen, they exposed to unfavorable microclimate, higher level of noise, vibration and their work was classified as heavy. Also, traffic policemen presented subjective complaints about negative impact of polluted air of motorways on their health status. Prevalence of chronic diseases was analyzed in group of 431 traffic policemen. The authors revealed a leading role of the following diseases: musculoskeletal diseases, diseases of connective tissue, digestive diseases, diseases of the nerve system, circulation system; their portion in the morbidity structure was 86.0%. The association of these diseases with occupation was confirmed by the increasing of their incidence with increasing of length of duration of service. Calculation of indices of relative occupational risk showed (that especially important) the increase of the length of service led to the increase in the risk ofpathologies, in which stress played a significant role. In examined group, the authors revealed such diseases as hypertension, autonomous-vascular dystonia, gastric and duodenal ulcer. Risk of the development of these diseases in some age/length of service groups is classified as high and very high. Obtained results provide the evidence that measures aimed to the decrease of the exposure to occupational factors will promote prevention of stress-stipulated diseases among traffic policemen.

The Histone Chaperone NRP1 Interacts with WEREWOLF to Activate GLABRA2 in Arabidopsis Root Hair Development.

PubMed

Zhu, Yan; Rong, Liang; Luo, Qiang; Wang, Baihui; Zhou, Nana; Yang, Yue; Zhang, Chi; Feng, Haiyang; Zheng, Lina; Shen, Wen-Hui; Ma, Jinbiao; Dong, Aiwu

2017-02-01

NUCLEOSOME ASSEMBLY PROTEIN1 (NAP1) defines an evolutionarily conserved family of histone chaperones and loss of function of the Arabidopsis thaliana NAP1 family genes NAP1-RELATED PROTEIN1 ( NRP1 ) and NRP2 causes abnormal root hair formation. Yet, the underlying molecular mechanisms remain unclear. Here, we show that NRP1 interacts with the transcription factor WEREWOLF (WER) in vitro and in vivo and enriches at the GLABRA2 ( GL2 ) promoter in a WER-dependent manner. Crystallographic analysis indicates that NRP1 forms a dimer via its N-terminal α-helix. Mutants of NRP1 that either disrupt the α-helix dimerization or remove the C-terminal acidic tail, impair its binding to histones and WER and concomitantly lead to failure to activate GL2 transcription and to rescue the nrp1-1 nrp2-1 mutant phenotype. Our results further demonstrate that WER-dependent enrichment of NRP1 at the GL2 promoter is involved in local histone eviction and nucleosome loss in vivo. Biochemical competition assays imply that the association between NRP1 and histones may counteract the inhibitory effect of histones on the WER-DNA interaction. Collectively, our study provides important insight into the molecular mechanisms by which histone chaperones are recruited to target chromatin via interaction with a gene-specific transcription factor to moderate chromatin structure for proper root hair development. © 2017 American Society of Plant Biologists. All rights reserved.

[Mathematic analysis of risk factors influence on occupational respiratory diseases development].

PubMed

Budkar', L N; Bugaeva, I V; Obukhova, T Iu; Tereshina, L G; Karpova, E A; Shmonina, O G

2010-01-01

Analysis covered 1348 case histories of workers exposed to industrial dust in Urals region. The analysis applied mathematical processing of survival theory and correlation analysis. The authors studied influence of various factors: dust concentration, connective tissue dysplasia, smoking habits--on duration for diseases caused by dust to appear. Findings are that occupational diseases develop reliably faster with higher ambient dust concentrations and with connective tissue dysplasia syndrome. Smoking habits do not alter duration of pneumoconiosis development, but reliably increases development of occupational dust bronchitis.

Role of the histone deacetylase complex in acute promyelocytic leukaemia.

PubMed

Lin, R J; Nagy, L; Inoue, S; Shao, W; Miller, W H; Evans, R M

1998-02-19

Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex through a class of silencing mediators termed SMRT or N-CoR. Mutant forms of RARalpha, created by chromosomal translocations with either the PML (for promyelocytic leukaemia) or the PLZF (for promyelocytic leukaemia zinc finger) locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML-RARalpha APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF-RARalpha patients respond very poorly, if at all. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.

No need to be HAMLET or BAMLET to interact with histones: binding of monomeric alpha-lactalbumin to histones and basic poly-amino acids.

PubMed

Permyakov, Serge E; Pershikova, Irina V; Khokhlova, Tatyana I; Uversky, Vladimir N; Permyakov, Eugene A

2004-05-18

The ability of a specific complex of human alpha-lactalbumin with oleic acid (HAMLET) to induce cell death with selectivity for tumor and undifferentiated cells was shown recently to be mediated by interaction of HAMLET with histone proteins irreversibly disrupting chromatin structure [Duringer, C., et al. (2003) J. Biol. Chem. 278, 42131-42135]. Here we show that monomeric alpha-lactalbumin (alpha-LA) in the absence of fatty acids is also able to bind efficiently to the primary target of HAMLET, histone HIII, regardless of Ca(2+) content. Thus, the modification of alpha-LA by oleic acid is not required for binding to histones. We suggest that interaction of negatively charged alpha-LA with the basic histone stabilizes apo-alpha-LA and destabilizes the Ca(2+)-bound protein due to compensation for excess negative charge of alpha-LA's Ca(2+)-binding loop by positively charged residues of the histone. Spectrofluorimetric curves of titration of alpha-LA by histone H3 were well approximated by a scheme of cooperative binding of four alpha-LA molecules per molecule of histone, with an equilibrium dissociation constant of 1.0 microM. Such a stoichiometry of binding implies that the binding process is not site-specific with respect to histone and likely is driven by just electrostatic interactions. Co-incubation of positively charged poly-amino acids (poly-Lys and poly-Arg) with alpha-LA resulted in effects which were similar to those caused by histone HIII, confirming the electrostatic nature of the alpha-LA-histone interaction. In all cases that were studied, the binding was accompanied by aggregation. The data indicate that alpha-lactalbumin can be used as a basis for the design of antitumor agents, acting through disorganization of chromatin structure due to interaction between alpha-LA and histone proteins.

Beyond the walls of the nucleus: the role of histones in cellular signaling and innate immunity.

PubMed

Parseghian, Missag H; Luhrs, Keith A

2006-08-01

Although they are one of the oldest family of proteins known (first described in 1884 by Kossel), histones continue to surprise researchers with their ever expanding roles in biology. In the past 25 years, the view of core histone octamers as a simple spool around which DNA in the nucleus is wound and linker histones as mere fasteners clipping it all together has transformed into the realization that histones play a vital role in transcriptional regulation. Through post-translational modifications, histones control the accessibility of transcription factors and a host of other proteins to multiple, conceivably thousands of, genes at once. While researchers have spent decades deciphering the role of histones in the overall structure of chromatin, it might surprise some to find that an entirely separate faction of scientists have focused on the role of histones beyond the confines of the nuclear envelope. In the past decade, there has been an accumulation of observations that suggest that histones can be found at the mitochondrion during the onset of apoptotic signaling and even at the cell surface, acting as a receptor for bacterial and viral proteins. More provocatively, immunologists are becoming convinced that they can also be found in the lumen of several tissues, acting as antimicrobial agents--critical components of an ancient innate immune system. Perhaps nowhere is this observation as dramatic as in the ability of neutrophils to entrap bacterial pathogens by casting out "nets" of DNA and histones that not only act as a physical barrier, but also display bactericidal activity. As our views regarding the role of histones inside and outside the cell evolve, some have begun to develop therapies that either utilize or target histones in the fight against cancer, microbial infection, and autoimmune disease. It is our goal here to begin the process of merging the dichotomous lives of histones both within and without the nuclear membrane.

Risk Factors for Breast Cancer, Including Occupational Exposures

PubMed Central

Meo, Margrethe; Vainio, Harri

2011-01-01

The knowledge on the etiology of breast cancer has advanced substantially in recent years, and several etiological factors are now firmly established. However, very few new discoveries have been made in relation to occupational risk factors. The International Agency for Research on Cancer has evaluated over 900 different exposures or agents to-date to determine whether they are carcinogenic to humans. These evaluations are published as a series of Monographs (www.iarc.fr). For breast cancer the following substances have been classified as "carcinogenic to humans" (Group 1): alcoholic beverages, exposure to diethylstilbestrol, estrogen-progestogen contraceptives, estrogen-progestogen hormone replacement therapy and exposure to X-radiation and gamma-radiation (in special populations such as atomic bomb survivors, medical patients, and in-utero exposure). Ethylene oxide is also classified as a Group 1 carcinogen, although the evidence for carcinogenicity in epidemiologic studies, and specifically for the human breast, is limited. The classification "probably carcinogenic to humans" (Group 2A) includes estrogen hormone replacement therapy, tobacco smoking, and shift work involving circadian disruption, including work as a flight attendant. If the association between shift work and breast cancer, the most common female cancer, is confirmed, shift work could become the leading cause of occupational cancer in women. PMID:22953181

Histone H1 chaperone activity of TAF-I is regulated by its subtype-dependent intramolecular interaction.

PubMed

Kajitani, Kaori; Kato, Kohsuke; Nagata, Kyosuke

2017-04-01

Linker histone H1 is involved in the regulation of gene activity through the maintenance of higher-order chromatin structure. Previously, we have shown that template activating factor-I (TAF-I or protein SET) is involved in linker histone H1 dynamics as a histone H1 chaperone. In human and murine cells, two TAF-I subtypes exist, namely TAF-Iα and TAF-Iβ. TAF-I has a highly acidic amino acid cluster in its C-terminal region and forms homo- or heterodimers through its dimerization domain. Both dimer formation and the C-terminal region of TAF-I are essential for the histone chaperone activity. TAF-Iα exhibits less histone chaperone activity compared with TAF-Iβ even though TAF-Iα and β differ only in their N-terminal regions. However, it is unclear how subtype-specific TAF-I activities are regulated. Here, we have shown that the N-terminal region of TAF-Iα autoinhibits its histone chaperone activity via intramolecular interaction with its C-terminal region. When the interaction between the N- and C-terminal regions of TAF-Iα is disrupted, TAF-Iα shows a histone chaperone activity similar to that of TAF-Iβ. Taken together, these results provide mechanistic insights into the concept that fine tuning of TAF-I histone H1 chaperone activity relies on the subtype compositions of the TAF-I dimer. © 2017 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

Ubiquitous and gene-specific regulatory 5' sequences in a sea urchin histone DNA clone coding for histone protein variants.

PubMed Central

Busslinger, M; Portmann, R; Irminger, J C; Birnstiel, M L

1980-01-01

The DNA sequences of the entire structural H4, H3, H2A and H2B genes and of their 5' flanking regions have been determined in the histone DNA clone h19 of the sea urchin Psammechinus miliaris. In clone h19 the polarity of transcription and the relative arrangement of the histone genes is identical to that in clone h22 of the same species. The histone proteins encoded by h19 DNA differ in their primary structure from those encoded by clone h22 and have been compared to histone protein sequences of other sea urchin species as well as other eukaryotes. A comparative analysis of the 5' flanking DNA sequences of the structural histone genes in both clones revealed four ubiquitous sequence motifs; a pentameric element GATCC, followed at short distance by the Hogness box GTATAAATAG, a conserved sequence PyCATTCPu, in or near which the 5' ends of the mRNAs map in h22 DNA and lastly a sequence A, containing the initiation codon. These sequences are also found, sometimes in modified version, in front of other eukaryotic genes transcribed by polymerase II. When prelude sequences of isocoding histone genes in clone h19 and h22 are compared areas of homology are seen to extend beyond the ubiquitous sequence motifs towards the divergent AT-rich spacer and terminate between approximately 140 and 240 nucleotides away from the structural gene. These prelude regions contain quite large conservative sequence blocks which are specific for each type of histone genes. Images PMID:7443547

Occupational factors and reproductive outcomes among a cohort of female veterinarians.

PubMed

Wilkins, J R; Steele, L L

1998-07-01

To estimate absolute and relative risks of preterm delivery (PTD) and small-for-gestational-age (SGA) births among a cohort of female veterinarians in relation to selected occupational factors, including clinical practice type (CPT). Retrospective cohort survey. 2,997 female graduates from US veterinary colleges between 1970 and 1980. Relevant health and occupational data were collected through a self-administered mail questionnaire with telephone follow-up of nonrespondents. Absolute and relative risks of PTD and SGA births were estimated in relation to maternal CPT at the time of conception and exposure to 13 occupational factors. Attempts were made to control confounding by use of multiple logistic regression analyses. Absolute and relative risks of PTD were highest for veterinarians employed in exclusively equine clinical practice. Although several increased, none of the CPT-specific relative risk estimates were significantly different from the null value of 1. Exposure-specific analyses indicated that occupational involvement with solvents among exclusively small animal practitioners was associated with the highest relative risk of PTD. A small number of SGA births limited information that could be obtained from these analyses. Overall absolute risks of PTD and SGA births among cohort members were much lower in comparison with the general female population. Given the large number of women currently practicing and entering the profession of veterinary medicine, clinical tasks associated with potential reproductive hazards should be approached with heightened awareness and increased caution, especially activities that may involve exposure to solvents.

Histone deacetylase inhibitors promote the tumoricidal effect of HAMLET.

PubMed

Brest, Patrick; Gustafsson, Mattias; Mossberg, Ann-Kristin; Gustafsson, Lotta; Duringer, Caroline; Hamiche, Ali; Svanborg, Catharina

2007-12-01

Histone deacetylase inhibitors (HDIs) and HAMLET (human alpha-lactalbumin made lethal to tumor cells) interact with histones, modify the structure of chromatin, and trigger tumor cell death. This study investigated how the combination of HDIs and HAMLET influences cell viability, histone acetylation, and DNA integrity. The pretreatment of tumor cells with HDIs was shown to enhance the lethal effect of HAMLET and the histone hyperacetylation response to HDIs increased even further after HAMLET treatment. HDIs and HAMLET were shown to target different histone domains as HAMLET bound tailless core histones, whereas HDIs modify the acetylation of the histone tail. DNA damage in response to HAMLET was increased by HDIs. The DNA repair response (p21WAFI expression) was induced by both agonists but abolished when the two agonists were combined. The results suggest that the synergy of HDIs and HAMLET is based on different but converging death pathways, both involving chromatin alterations. We speculate that HAMLET and HDIs might be combined to promote tumor cell death in vivo.

Musculoskeletal pain in Europe: role of personal, occupational and social risk factors

PubMed Central

Farioli, Andrea; Mattioli, Stefano; Quaglieri, Anna; Curti, Stefania; Violante, Francesco S; Coggon, David

2014-01-01

Objectives Prevalence of musculoskeletal pain in European countries varies considerably. We analyzed data from the fifth European Working Conditions Survey (EWCS) to explore the role of personal, occupational, and social risk factors in determining the national prevalence of musculoskeletal pain. Methods During 2010, 43,816 subjects from 34 countries were interviewed. We analyzed the one-year prevalence of back and neck/upper limb pain. Personal risk factors studied were: sex; age; educational level; socio-economic status; housework or cooking; gardening and repairs; somatising tendency; job demand-control; six physical occupational exposures; and occupational group. Data on national socio-economic risk factors were obtained from eurostat and were available for 29 countries. We fitted Poisson regression models with random intercept on country. Results 35,550 workers entered the main analysis. Among personal risk factors, somatising tendency was the strongest predictor of the symptoms. Major differences were observed by country with back pain more than twice as common in Portugal (63.8%) as Ireland (25.7%), and prevalence rates of neck/upper limb pain ranging from 26.6% in Ireland to 67.7% in Finland. Adjustment by personal risk factors slightly reduced the large variation of prevalence between countries. For back pain, the rates were more homogenous after adjustment for social risk factors. Conclusions Our analysis indicates substantial variation between European countries in the prevalence of back and neck/upper limb pain. This variation is unexplained by established individual risk factors. It may be attributable in part to socio-economic differences between countries, with higher prevalence where there is less poverty and more social support. PMID:24009006

SET oncoprotein accumulation regulates transcription through DNA demethylation and histone hypoacetylation.

PubMed

Almeida, Luciana O; Neto, Marinaldo P C; Sousa, Lucas O; Tannous, Maryna A; Curti, Carlos; Leopoldino, Andreia M

2017-04-18

Epigenetic modifications are essential in the control of normal cellular processes and cancer development. DNA methylation and histone acetylation are major epigenetic modifications involved in gene transcription and abnormal events driving the oncogenic process. SET protein accumulates in many cancer types, including head and neck squamous cell carcinoma (HNSCC); SET is a member of the INHAT complex that inhibits gene transcription associating with histones and preventing their acetylation. We explored how SET protein accumulation impacts on the regulation of gene expression, focusing on DNA methylation and histone acetylation. DNA methylation profile of 24 tumour suppressors evidenced that SET accumulation decreased DNA methylation in association with loss of 5-methylcytidine, formation of 5-hydroxymethylcytosine and increased TET1 levels, indicating an active DNA demethylation mechanism. However, the expression of some suppressor genes was lowered in cells with high SET levels, suggesting that loss of methylation is not the main mechanism modulating gene expression. SET accumulation also downregulated the expression of 32 genes of a panel of 84 transcription factors, and SET directly interacted with chromatin at the promoter of the downregulated genes, decreasing histone acetylation. Gene expression analysis after cell treatment with 5-aza-2'-deoxycytidine (5-AZA) and Trichostatin A (TSA) revealed that histone acetylation reversed transcription repression promoted by SET. These results suggest a new function for SET in the regulation of chromatin dynamics. In addition, TSA diminished both SET protein levels and SET capability to bind to gene promoter, suggesting that administration of epigenetic modifier agents could be efficient to reverse SET phenotype in cancer.

Stable-isotope-labeled Histone Peptide Library for Histone Post-translational Modification and Variant Quantification by Mass Spectrometry *

PubMed Central

Lin, Shu; Wein, Samuel; Gonzales-Cope, Michelle; Otte, Gabriel L.; Yuan, Zuo-Fei; Afjehi-Sadat, Leila; Maile, Tobias; Berger, Shelley L.; Rush, John; Lill, Jennie R.; Arnott, David; Garcia, Benjamin A.

2014-01-01

To facilitate accurate histone variant and post-translational modification (PTM) quantification via mass spectrometry, we present a library of 93 synthetic peptides using Protein-Aqua™ technology. The library contains 55 peptides representing different modified forms from histone H3 peptides, 23 peptides representing H4 peptides, 5 peptides representing canonical H2A peptides, 8 peptides representing H2A.Z peptides, and peptides for both macroH2A and H2A.X. The PTMs on these peptides include lysine mono- (me1), di- (me2), and tri-methylation (me3); lysine acetylation; arginine me1; serine/threonine phosphorylation; and N-terminal acetylation. The library was subjected to chemical derivatization with propionic anhydride, a widely employed protocol for histone peptide quantification. Subsequently, the detection efficiencies were quantified using mass spectrometry extracted ion chromatograms. The library yields a wide spectrum of detection efficiencies, with more than 1700-fold difference between the peptides with the lowest and highest efficiencies. In this paper, we describe the impact of different modifications on peptide detection efficiencies and provide a resource to correct for detection biases among the 93 histone peptides. In brief, there is no correlation between detection efficiency and molecular weight, hydrophobicity, basicity, or modification type. The same types of modifications may have very different effects on detection efficiencies depending on their positions within a peptide. We also observed antagonistic effects between modifications. In a study of mouse trophoblast stem cells, we utilized the detection efficiencies of the peptide library to correct for histone PTM/variant quantification. For most histone peptides examined, the corrected data did not change the biological conclusions but did alter the relative abundance of these peptides. For a low-abundant histone H2A variant, macroH2A, the corrected data led to a different conclusion than the

Occupational safety threats among dental personnel and related risk factors.

PubMed

Gurbuz, M Kezban; Çatli, Tolgahan; Cingi, Cemal; Yaz, Aytekin; Bal, Cengiz

2013-11-01

Occupational diseases are primarily considered to be important health problems for individuals with occupations in heavy industry fields. Although dentists work in very clean and elegant offices, they are frequently exposed to various chemicals and high-intensity, sound-producing instruments, such as compressors and aerators. In our study, we aimed to investigate the risk for occupational hearing loss of dental personnel, by performing pure-tone audiometry in 40 dentists and comparing the results with those of healthy individuals. We also sampled the nasal mucosa to investigate the effects of occupational chemicals on the nasal mucosa of the dentists. The pure-tone audiometric thresholds at 5 different frequencies (1000, 2000, 4000, 6000, and 8000 Hz) and working time were evaluated as potential risk factors. The pure-tone audiometric results (as decibels) at each frequency and the median values for each side (right and left ears) were significantly higher for dentists than for the control group (P < 0.05). The pure-tone audiometric results did not significantly differ between the women and men in the study group (P > 0.05). The findings in the nasal mucosa (goblet cell hyperplasia, neutrophil/eosinophil/basophil distribution, metaplasia, dysplasia, premalignant or malignant cells) were similar in the study and control groups (P > 0.05). In conclusion, our study indicated that high-intensity, sound-producing equipment is an important occupational threat for dentists, whereas chemical agents have minimal hazardous effects.

Epigenetic Mechanisms Impacting Aging: A Focus on Histone Levels and Telomeres

PubMed Central

Song, Shufei

2018-01-01

Aging and age-related diseases pose some of the most significant and difficult challenges to modern society as well as to the scientific and medical communities. Biological aging is a complex, and, under normal circumstances, seemingly irreversible collection of processes that involves numerous underlying mechanisms. Among these, chromatin-based processes have emerged as major regulators of cellular and organismal aging. These include DNA methylation, histone modifications, nucleosome positioning, and telomere regulation, including how these are influenced by environmental factors such as diet. Here we focus on two interconnected categories of chromatin-based mechanisms impacting aging: those involving changes in the levels of histones or in the functions of telomeres. PMID:29642537

Protein kinase D2 controls cardiac valve formation in zebrafish by regulating histone deacetylase 5 activity.

PubMed

Just, Steffen; Berger, Ina M; Meder, Benjamin; Backs, Johannes; Keller, Andreas; Marquart, Sabine; Frese, Karen; Patzel, Eva; Rauch, Gerd-Jörg; Katus, Hugo A; Rottbauer, Wolfgang

2011-07-19

The molecular mechanisms that guide heart valve formation are not well understood. However, elucidation of the genetic basis of congenital heart disease is one of the prerequisites for the development of tissue-engineered heart valves. We isolated here a mutation in zebrafish, bungee (bng(jh177)), which selectively perturbs valve formation in the embryonic heart by abrogating endocardial Notch signaling in cardiac cushions. We found by positional cloning that the bng phenotype is caused by a missense mutation (Y849N) in zebrafish protein kinase D2 (pkd2). The bng mutation selectively impairs PKD2 kinase activity and hence Histone deacetylase 5 phosphorylation, nuclear export, and inactivation. As a result, the expression of Histone deacetylase 5 target genes Krüppel-like factor 2a and 4a, transcription factors known to be pivotal for heart valve formation and to act upstream of Notch signaling, is severely downregulated in bungee (bng) mutant embryos. Accordingly, the expression of Notch target genes, such as Hey1, Hey2, and HeyL, is severely decreased in bng mutant embryos. Remarkably, downregulation of Histone deacetylase 5 activity in homozygous bng mutant embryos can rescue the mutant phenotype and reconstitutes notch1b expression in atrioventricular endocardial cells. We demonstrate for the first time that proper heart valve formation critically depends on Protein kinase D2-Histone deacetylase 5-Krüppel-like factor signaling.

The contribution of occupational factors to social inequalities in health: findings from the national French SUMER survey.

PubMed

Niedhammer, Isabelle; Chastang, Jean-François; David, Simone; Kelleher, Cecily

2008-12-01

Social inequalities in health have long been demonstrated, but the understanding of these inequalities remains unclear. Work and its related occupational factors may contribute to these inequalities. The objective of this study was to study the contribution of work factors using an integrated approach (including all types of exposures) to social inequalities in three health outcomes: poor self-reported health, long sickness absence, and work injury. Respondents were 14,241 men and 10,245 women drawn from a survey of the national French working population (response rate: 96.5%). Work factors included job characteristics, and occupational exposures of the physical, ergonomic, biological, chemical, and psychosocial work environment. All work factors were measured through expert evaluation by occupational physicians, except psychosocial work factors, which were self-reported. Strong social gradients were found for all work factors, except for psychological demands, workplace bullying, and aggression from the public. Marked social gradients were also observed for the health outcomes studied, blue collar workers being more likely to report poor self-reported health, long sickness absence, and work injury. The social differences in health were reduced strongly after adjustment for work factors (psychological demands excluded) by 24-58% according to sex and health outcomes. The strongest impacts were found for decision latitude, ergonomic, physical, and chemical exposures, as well as for work schedules. A detailed analysis allowed us to identify more precisely the contributing occupational factors. It suggests that concerted prevention of occupational risk factors would be useful not only to improve health at work, but also to reduce social inequalities in health.

Effects of histone acetylation and DNA methylation on p21( WAF1) regulation.

PubMed

Fang, Jing-Yuan; Lu, You-Yong

2002-06-01

Cell cycle progression is regulated by interactions between cyclins and cyclin-dependent kinases (CDKs). p21(WAF1) is one of the CIP/KIP family which inhibits CDKs activity. Increased expression of p21(WAF1) may play an important role in the growth arrest induced in transformed cells. Although the stability of the p21( WAF1) mRNA could be altered by different signals, cell differentiation and numerous influencing factors. However, recent studies suggest that two known mechanisms of epigenesis, i.e.gene inactivation by methylation in promoter region and changes to an inactive chromatin by histone deacetylation, seem to be the best candidate mechanisms for inactivation of p21( WAF1). To date, almost no coding region p21(WAF1) mutations have been found in tumor cells, despite extensive screening of hundreds of various tumors. Hypermethylation of the p21(WAF1) promoter region may represent an alternative mechanism by which the p21(WAF1/CIP1) gene can be inactivated. The reduction of cellular DNMT protein levels also induces a corresponding rapid increase in the cell cycle regulator p21(WAF1) protein demonstrating a regulatory link between DNMT and p21(WAF1) which is independent of methylation of DNA. Both histone hyperacetylation and hypoacetylation appear to be important in the carcinoma process, and induction of the p21(WAF1) gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis. Here, we review the influence of histone acetylation and DNA methylation on p21(WAF1) transcription, and affection of pathways or factors associated such as p 53, E2A, Sp1 as well as several histone deacetylation inhibitors.

Prevalence of musculoskeletal disorders and related occupational causative factors among electricity linemen: A narrative review.

PubMed

Padmanathan, Vinothini; Joseph, Leonard; Omar, Baharudin; Nawawi, Roslizawati

2016-01-01

Occupational tasks of linemen are highly associated with the development of work related musculoskeletal disorders (WRMDs). Although linemen are prone to develop WRMDs, there is paucity of information on the prevalence of WRMDs and related occupational causative factors. Therefore, the present review was conducted to report on the prevalence of WRMDs and to outline causative risk factors within occupational tasks in the lineman profession. Literature search was conducted in various databases such as Scopus, PubMed and ScienceDirect for articles published between 1996-2013. The articles were analyzed, selected and retrieved based on predetermined objectives, inclusion criteria and Medical Subject Headings (MeSH). In the review process only articles published in English were considered. The review identified moderate to high prevalence of WRMDs among the linemen population. Back and shoulder regions were highly affected compared to the other body regions. The review also reported occupational tasks such as bar installation, insulator fixation and manual handling of tools as high risk tasks that lead to the development of WRMDs. In addition, occupational tools such as ladders, manual cutters and manual presses were also identified as a potential ergonomic hazard. In conclusion, the current review identified that WRMDs are common in the back and shoulder regions among linemen. Also, a number of occupational risk factors were identified to be associated with WRMDs among the linemen. Hence, future research on prevention and intervention studies concerning lineman profession population in order to develop a good job practice are recommended. Int J Occup Med Environ Health 2016;29(5):725-734. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

The histone acetyltransferase MOF overexpression blunts cardiac hypertrophy by targeting ROS in mice.

PubMed

Qiao, Weiwei; Zhang, Weili; Gai, Yusheng; Zhao, Lan; Fan, Juexin

2014-06-13

Imbalance between histone acetylation/deacetylation critically participates in the expression of hypertrophic fetal genes and development of cardiac hypertrophy. While histone deacetylases play dual roles in hypertrophy, current evidence reveals that histone acetyltransferase such as p300 and PCAF act as pro-hypertrophic factors. However, it remains elusive whether some histone acetyltransferases can prevent the development of hypertrophy. Males absent on the first (MOF) is a histone acetyltransferase belonging to the MYST (MOZ, Ybf2/Sas3, Sas2 and TIP60) family. Here in this study, we reported that MOF expression was down-regulated in failing human hearts and hypertrophic murine hearts at protein and mRNA levels. To evaluate the roles of MOF in cardiac hypertrophy, we generated cardiac-specific MOF transgenic mice. MOF transgenic mice did not show any differences from their wide-type littermates at baseline. However, cardiac-specific MOF overexpression protected mice from transverse aortic constriction (TAC)-induced cardiac hypertrophy, with reduced radios of heart weight (HW)/body weight (BW), lung weight/BW and HW/tibia length, decreased left ventricular wall thickness and increased fractional shortening. We also observed lower expression of hypertrophic fetal genes in TAC-challenged MOF transgenic mice compared with that of wide-type mice. Mechanically, MOF overexpression increased the expression of Catalase and MnSOD, which blocked TAC-induced ROS and ROS downstream c-Raf-MEK-ERK pathway that promotes hypertrophy. Taken together, our findings identify a novel anti-hypertrophic role of MOF, and MOF is the first reported anti-hypertrophic histone acetyltransferase. Copyright © 2014 Elsevier Inc. All rights reserved.

Antibodies against H3 and H4 histones from the sera of HIV-infected patients catalyze site-specific degradation of these histones.

PubMed

Baranova, Svetlana V; Dmitrenok, Pavel S; Zubkova, Anastasiya D; Ivanisenko, Nikita V; Odintsova, Elena S; Buneva, Valentina N; Nevinsky, Georgy A

2018-02-19

Histones and their posttranslational modified forms play pivotal roles in chromatin functioning and gene transcription. Also, histones are harmful when they enter the intercellular space; their administration to animals results in systemic inflammatory and toxic responses. Autoantibodies having enzymatic activities (abzymes) are the specific feature of several autoimmune and viral diseases. Electrophoretically homogeneous IgGs containing no canonical proteases were purified from sera of HIV-infected patients by using several affinity chromatographies. In contrast to known canonical proteases, Abs from HIV-infected patients hydrolyzed exclusively only histones but no other control globular proteins. The H3 and H4 histone cleavage sites by antihistone IgGs were determined by matrix-assisted laser desorption/ionization mass spectrometry for the first time. Two clusters of H3 hydrolysis contain major (↕) and minor (*) cleavage sites: 18-K*Q*LA↕TK*A↕AR*KS↕A*P-30 and 34-G*VK*KPHR*YRPGTVA*L*R-50. H4 histone has only 1 cluster of cleavage sites containing additionally moderate (↓) cleavage sites: 15-A↕KR↕HR↕KVLR↓D*NIQ↓GIT*K-31. Sites of these histones cleavage correspond mainly to their known epitopes. It was surprising that most of the cleavage sites of histones are involved in the interaction with DNA of nucleosome core. Because histones act as damage-associated molecules, abzymes against H3 and H4 can play important role in pathogenesis of AIDs and probably other viral and immune diseases. Copyright © 2018 John Wiley & Sons, Ltd.

Dietary histone deacetylase inhibitors

PubMed Central

Dashwood, Roderick H.; Ho, Emily

2009-01-01

Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables, such as broccoli and broccoli sprouts. This anticarcinogen was first identified as a potent inducer of Phase 2 detoxification enzymes, but evidence is mounting that SFN also acts through epigenetic mechanisms. SFN has been shown to inhibit histone deacetylase (HDAC) activity in human colon and prostate cancer lines, with an increase in global and local histone acetylation status, such as on the promoter regions of P21 and bax genes. SFN also inhibited the growth of prostate cancer xenografts and spontaneous intestinal polyps in mouse models, with evidence for altered histone acetylation and HDAC activities in vivo. In human subjects, a single ingestion of 68 g broccoli sprouts inhibited HDAC activity in circulating peripheral blood mononuclear cells 3-6 h after consumption, with concomitant induction of histone H3 and H4 acetylation. These findings provide evidence that one mechanism of cancer chemoprevention by SFN is via epigenetic changes associated with inhibition of HDAC activity. Other dietary agents such as butyrate, biotin, lipoic acid, garlic organosulfur compounds, and metabolites of vitamin E have structural features compatible with HDAC inhibition. The ability of dietary compounds to de-repress epigenetically silenced genes in cancer cells, and to activate these genes in normal cells, has important implications for cancer prevention and therapy. In a broader context, there is growing interest in dietary HDAC inhibitors and their impact on epigenetic mechanisms affecting other chronic conditions, such as cardiovascular disease, neurodegeneration and aging. PMID:17555985

A NAP-Family Histone Chaperone Functions in Abiotic Stress Response and Adaptation1[OPEN

PubMed Central

Pareek, Ashwani; Singla-Pareek, Sneh Lata

2016-01-01

Modulation of gene expression is one of the most significant molecular mechanisms of abiotic stress response in plants. Via altering DNA accessibility, histone chaperones affect the transcriptional competence of genomic loci. However, in contrast to other factors affecting chromatin dynamics, the role of plant histone chaperones in abiotic stress response and adaptation remains elusive. Here, we studied the physiological function of a stress-responsive putative rice (Oryza sativa) histone chaperone of the NAP superfamily: OsNAPL6. We show that OsNAPL6 is a nuclear-localized H3/H4 histone chaperone capable of assembling a nucleosome-like structure. Utilizing overexpression and knockdown approaches, we found a positive correlation between OsNAPL6 expression levels and adaptation to multiple abiotic stresses. Results of comparative transcriptome profiling and promoter-recruitment studies indicate that OsNAPL6 functions during stress response via modulation of expression of various genes involved in diverse functions. For instance, we show that OsNAPL6 is recruited to OsRad51 promoter, activating its expression and leading to more efficient DNA repair and abrogation of programmed cell death under salinity and genotoxic stress conditions. These results suggest that the histone chaperone OsNAPL6 may serve a regulatory role in abiotic stress physiology possibly via modulating nucleosome dynamics at various stress-associated genomic loci. Taken together, our findings establish a hitherto unknown link between histone chaperones and abiotic stress response in plants. PMID:27342307

Murine hematopoietic stem cell dormancy controlled by induction of a novel short form of PSF1 by histone deacetylase inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, Yinglu; Gong, Zhi-Yuan; Takakura, Nobuyuki, E-mail: ntakaku@biken.osaka-u.ac.jp

2015-06-10

Hematopoietic stem cells (HSCs) can survive long-term in a state of dormancy. Little is known about how histone deacetylase inhibitors (HDACi) affect HSC kinetics. Here, we use trichostatin A (TSA), a histone deacetylase inhibitor, to enforce histone acetylation and show that this suppresses cell cycle entry by dormant HSCs. Previously, we found that haploinsufficiency of PSF1, a DNA replication factor, led to attenuation of the bone marrow (BM) HSC pool size and lack of acute proliferation after 5-FU ablation. Because PSF1 protein is present in CD34{sup +} transiently amplifying HSCs but not in CD34{sup −} long-term reconstituting-HSCs which are restingmore » in a dormant state, we analyzed the relationship between dormancy and PSF1 expression, and how a histone deacetylase inhibitor affects this. We found that CD34{sup +} HSCs produce long functional PSF1 (PSF1a) but CD34{sup −} HSCs produce a shorter possibly non-functional PSF1 (PSF1b, c, dominantly PSF1c). Using PSF1a-overexpressing NIH-3T3 cells in which the endogenous PSF1 promoter is suppressed, we found that TSA treatment promotes production of the shorter form of PSF1 possibly by inducing recruitment of E2F family factors upstream of the PSF1 transcription start site. Our data document one mechanism by which histone deacetylase inhibitors affect the dormancy of HSCs by regulating the DNA replication factor PSF1. - Highlights: • Hematopoetic stem cell dormancy is controlled by histone deacetylation inhibitors. • Dormancy of HSCs is associated with a shorter form of non-functional PSF1. • Histone deacetylase inhibitors suppress PSF1 promoter activity.« less

Detection of histone modifications in plant leaves.

PubMed

Jaskiewicz, Michal; Peterhansel, Christoph; Conrath, Uwe

2011-09-23

Chromatin structure is important for the regulation of gene expression in eukaryotes. In this process, chromatin remodeling, DNA methylation, and covalent modifications on the amino-terminal tails of histones H3 and H4 play essential roles(1-2). H3 and H4 histone modifications include methylation of lysine and arginine, acetylation of lysine, and phosphorylation of serine residues(1-2). These modifications are associated either with gene activation, repression, or a primed state of gene that supports more rapid and robust activation of expression after perception of appropriate signals (microbe-associated molecular patterns, light, hormones, etc.)(3-7). Here, we present a method for the reliable and sensitive detection of specific chromatin modifications on selected plant genes. The technique is based on the crosslinking of (modified) histones and DNA with formaldehyde(8,9), extraction and sonication of chromatin, chromatin immunoprecipitation (ChIP) with modification-specific antibodies(9,10), de-crosslinking of histone-DNA complexes, and gene-specific real-time quantitative PCR. The approach has proven useful for detecting specific histone modifications associated with C(4;) photosynthesis in maize(5,11) and systemic immunity in Arabidopsis(3).

Histone Deacetylase Rpd3 Regulates Olfactory Projection Neuron Dendrite Targeting via the Transcription Factor Prospero

PubMed Central

Tea, Joy S.; Chihara, Takahiro; Luo, Liqun

2010-01-01

Compared to the mechanisms of axon guidance, relatively little is known about the transcriptional control of dendrite guidance. The Drosophila olfactory system with its stereotyped organization provides an excellent model to study the transcriptional control of dendrite wiring specificity. Each projection neuron (PN) targets its dendrites to a specific glomerulus in the antennal lobe and its axon stereotypically to higher brain centers. Using a forward genetic screen, we identified a mutation in Rpd3 that disrupts PN targeting specificity. Rpd3 encodes a class I histone deacetylase (HDAC) homologous to mammalian HDAC1 and HDAC2. Rpd3−/− PN dendrites that normally target to a dorsolateral glomerulus mistarget to medial glomeruli in the antennal lobe, and axons exhibit a severe overbranching phenotype. These phenotypes can be rescued by postmitotic expression of Rpd3 but not HDAC3, the only other class I HDAC in Drosophila. Furthermore, disruption of the atypical homeodomain transcription factor Prospero (Pros) yields similar phenotypes, which can be rescued by Pros expression in postmitotic neurons. Strikingly, overexpression of Pros can suppress Rpd3−/− phenotypes. Our study suggests a specific function for the general chromatin remodeling factor Rpd3 in regulating dendrite targeting in neurons, largely through the postmitotic action of the Pros transcription factor. PMID:20660276

Distinct self-interaction domains promote Multi Sex Combs accumulation in and formation of the Drosophila histone locus body.

PubMed

Terzo, Esteban A; Lyons, Shawn M; Poulton, John S; Temple, Brenda R S; Marzluff, William F; Duronio, Robert J

2015-04-15

Nuclear bodies (NBs) are structures that concentrate proteins, RNAs, and ribonucleoproteins that perform functions essential to gene expression. How NBs assemble is not well understood. We studied the Drosophila histone locus body (HLB), a NB that concentrates factors required for histone mRNA biosynthesis at the replication-dependent histone gene locus. We coupled biochemical analysis with confocal imaging of both fixed and live tissues to demonstrate that the Drosophila Multi Sex Combs (Mxc) protein contains multiple domains necessary for HLB assembly. An important feature of this assembly process is the self-interaction of Mxc via two conserved N-terminal domains: a LisH domain and a novel self-interaction facilitator (SIF) domain immediately downstream of the LisH domain. Molecular modeling suggests that the LisH and SIF domains directly interact, and mutation of either the LisH or the SIF domain severely impairs Mxc function in vivo, resulting in reduced histone mRNA accumulation. A region of Mxc between amino acids 721 and 1481 is also necessary for HLB assembly independent of the LisH and SIF domains. Finally, the C-terminal 195 amino acids of Mxc are required for recruiting FLASH, an essential histone mRNA-processing factor, to the HLB. We conclude that multiple domains of the Mxc protein promote HLB assembly in order to concentrate factors required for histone mRNA biosynthesis. © 2015 Terzo et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Human borna disease virus infection impacts host proteome and histone lysine acetylation in human oligodendroglia cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Xia; Department of Neurology, The Fifth People's Hospital of Shanghai, School of Medicine, Fudan University, Shanghai, 200240; Zhao, Libo

2014-09-15

Background: Borna disease virus (BDV) replicates in the nucleus and establishes persistent infections in mammalian hosts. A human BDV strain was used to address the first time, how BDV infection impacts the proteome and histone lysine acetylation (Kac) of human oligodendroglial (OL) cells, thus allowing a better understanding of infection-driven pathophysiology in vitro. Methods: Proteome and histone lysine acetylation were profiled through stable isotope labeling for cell culture (SILAC)-based quantitative proteomics. The quantifiable proteome was annotated using bioinformatics. Histone acetylation changes were validated by biochemistry assays. Results: Post BDV infection, 4383 quantifiable differential proteins were identified and functionally annotated tomore » metabolism pathways, immune response, DNA replication, DNA repair, and transcriptional regulation. Sixteen of the thirty identified Kac sites in core histones presented altered acetylation levels post infection. Conclusions: BDV infection using a human strain impacted the whole proteome and histone lysine acetylation in OL cells. - Highlights: • A human strain of BDV (BDV Hu-H1) was used to infect human oligodendroglial cells (OL cells). • This study is the first to reveal the host proteomic and histone Kac profiles in BDV-infected OL cells. • BDV infection affected the expression of many transcription factors and several HATs and HDACs.« less

Occupational and environmental risk factors for falls among workers in the healthcare sector.

PubMed

Drebit, Sharla; Shajari, Salomeh; Alamgir, Hasanat; Yu, Shicheng; Keen, Dave

2010-04-01

Falls are a leading cause of occupational injury for workers in healthcare, yet the risk factors of falls in this sector are understudied. Falls resulting in workers' compensation for time-loss from work from 2004-2007 for healthcare workers in British Columbia (BC) were extracted from a standardised incident-reporting database. Productive hours were derived from payroll data for the denominator to produce injury rates; relative risks were derived through Poisson regression modelling. A total of 411 falls were accepted for time-loss compensation. Compared to registered nurses, facility support workers (risk ratio (95% CI) = 6.29 (4.56-8.69)) and community health workers (6.58 (3.76-11.50)) were at high risk for falls. Falls predominantly occurred outdoors, in patients' rooms and kitchens depending on occupation and sub-sector. Slippery surfaces due to icy conditions or liquid contaminants were a leading contributing factor. Falls were more frequent in the colder months (January-March). The risk of falls varies by nature of work, location and worker demographics. The findings of this research will be useful for developing evidence-based interventions. STATEMENT OF RELEVANCE: Falls are a major cause of occupational injury for healthcare workers. This study examined risk factors including occupation type, workplace design, work setting, work organisation and environmental conditions in a large healthcare worker population in BC, Canada. The findings of this research should contribute towards developing evidence-based interventions.

Occupational factors and the incidence of cancer of the bladder in Canada.

PubMed Central

Risch, H A; Burch, J D; Miller, A B; Hill, G B; Steele, R; Howe, G R

1988-01-01

During 1979-82, a case-control study of occupational factors and urinary bladder cancer was conducted in Edmonton, Calgary, Toronto, and Kingston, Canada. A total of 826 histologically verified cases of cancer were individually matched by sex, age, and area of residence to 792 randomly selected population controls. Subjects were specifically asked about employment in several industries thought relevant to risk of bladder cancer. Information was also obtained on lifelong occupational history, with special attention given regarding exposures to fumes, dusts, smoke, and chemicals. In addition, subjects provided data on past medical and residential history, on intake of certain dietary items, and on exposure to tobacco and other lifestyle factors. Conditional logistic regression methods were used for the analysis. Under adjustment for cumulative lifetime cigarette consumption, it appeared that for both men and women, most of the occupational factors examined were not associated with significant alteration in risk of bladder cancer. For exposures during the period eight to 28 years before diagnosis, however, raised risk was suggested for men employed at least six months in the chemicals industry (odds ratio = 2.37, p = 0.004), in dye manufacturing or the dyeing of cloth (OR = 3.62 and 4.63, p = 0.041 and 0.035, respectively), as tailors (OR = 3.85, p = 0.015), or in jobs in which contact with diesel or traffic fumes occurred (OR = 1.69, p = 0.0008). Increased risk was also seen for men occupationally exposed to tars or asphalt (OR = 3.11, p = 0.019). This study then, at least for men, supports perhaps a few of the suspect industries as related to risk of bladder cancer. PMID:3395572

PHYTOCHROME INTERACTING FACTOR3 Associates with the Histone Deacetylase HDA15 in Repression of Chlorophyll Biosynthesis and Photosynthesis in Etiolated Arabidopsis Seedlings[W][OA

PubMed Central

Liu, Xuncheng; Chen, Chia-Yang; Wang, Ko-Ching; Luo, Ming; Tai, Ready; Yuan, Lianyu; Zhao, Minglei; Yang, Songguang; Tian, Gang; Cui, Yuhai; Hsieh, Hsu-Liang; Wu, Keqiang

2013-01-01

PHYTOCHROME INTERACTING FACTOR3 (PIF3) is a key basic helix-loop-helix transcription factor of Arabidopsis thaliana that negatively regulates light responses, repressing chlorophyll biosynthesis, photosynthesis, and photomorphogenesis in the dark. However, the mechanism for the PIF3-mediated transcription regulation remains largely unknown. In this study, we found that the REDUCED POTASSIUM DEPENDENCY3/HISTONE DEACETYLASE1-type histone deacetylase HDA15 directly interacted with PIF3 in vivo and in vitro. Genome-wide transcriptome analysis revealed that HDA15 acts mainly as a transcriptional repressor and negatively regulates chlorophyll biosynthesis and photosynthesis gene expression in etiolated seedlings. HDA15 and PIF3 cotarget to the genes involved in chlorophyll biosynthesis and photosynthesis in the dark and repress gene expression by decreasing the acetylation levels and RNA Polymerase II–associated transcription. The binding of HDA15 to the target genes depends on the presence of PIF3. In addition, PIF3 and HDA15 are dissociated from the target genes upon exposure to red light. Taken together, our results indicate that PIF3 associates with HDA15 to repress chlorophyll biosynthetic and photosynthetic genes in etiolated seedlings. PMID:23548744

Involvement of Retinoblastoma Protein and HBP1 in Histone H10 Gene Expression

PubMed Central

Lemercier, Claudie; Duncliffe, Kym; Boibessot, Isabelle; Zhang, Hui; Verdel, André; Angelov, Dimitar; Khochbin, Saadi

2000-01-01

The histone H10-encoding gene is expressed in vertebrates in differentiating cells during the arrest of proliferation. In the H10 promoter, a specific regulatory element, which we named the H4 box, exhibits features which implicate a role in mediating H10 gene expression in response to both differentiation and cell cycle control signals. For instance, within the linker histone gene family, the H4 box is found only in the promoters of differentiation-associated subtypes, suggesting that it is specifically involved in differentiation-dependent expression of these genes. In addition, an element nearly identical to the H4 box is conserved in the promoters of histone H4-encoding genes and is known to be involved in their cell cycle-dependent expression. The transcription factors interacting with the H10 H4 box were therefore expected to link differentiation-dependent expression of H10 to the cell cycle control machinery. The aim of this work was to identify such transcription factors and to obtain information concerning the regulatory pathway involved. Interestingly, our cloning strategy led to the isolation of a retinoblastoma protein (RB) partner known as HBP1. HBP1, a high-mobility group box transcription factor, interacted specifically with the H10 H4 box and moreover was expressed in a differentiation-dependent manner. We also showed that the HBP1-encoding gene is able to produce different forms of HBP1. Finally, we demonstrated that both HBP1 and RB were involved in the activation of H10 gene expression. We therefore propose that HBP1 mediates a link between the cell cycle control machinery and cell differentiation signals. Through modulating the expression of specific chromatin-associated proteins such as histone H10, HBP1 plays a vital role in chromatin remodeling events during the arrest of cell proliferation in differentiating cells. PMID:10958660

Role of histone deacetylases in pancreas: Implications for pathogenesis and therapy

PubMed Central

Klieser, Eckhard; Swierczynski, Stefan; Mayr, Christian; Schmidt, Johanna; Neureiter, Daniel; Kiesslich, Tobias; Illig, Romana

2015-01-01

In the last years, our knowledge of the pathogenesis in acute and chronic pancreatitis (AP/CP) as well as in pancreatic cancerogenesis has significantly diversified. Nevertheless, the medicinal therapeutic options are still limited and therapeutic success and patient outcome are poor. Epigenetic deregulation of gene expression is known to contribute to development and progression of AP and CP as well as of pancreatic cancer. Therefore, the selective inhibition of aberrantly active epigenetic regulators can be an effective option for future therapies. Histone deacetylases (HDACs) are enzymes that remove an acetyl group from histone tails, thereby causing chromatin compaction and repression of transcription. In this review we present an overview of the currently available literature addressing the role of HDACs in the pancreas and in pancreatic diseases. In pancreatic cancerogenesis, HDACs play a role in the important process of epithelial-mesenchymal-transition, ubiquitin-proteasome pathway and, hypoxia-inducible-factor-1-angiogenesis. Finally, we focus on HDACs as potential therapeutic targets by summarizing currently available histone deacetylase inhibitors. PMID:26691388

Germline-specific H1 variants: the "sexy" linker histones.

PubMed

Pérez-Montero, Salvador; Carbonell, Albert; Azorín, Fernando

2016-03-01

The eukaryotic genome is packed into chromatin, a nucleoprotein complex mainly formed by the interaction of DNA with the abundant basic histone proteins. The fundamental structural and functional subunit of chromatin is the nucleosome core particle, which is composed by 146 bp of DNA wrapped around an octameric protein complex formed by two copies of each core histone H2A, H2B, H3, and H4. In addition, although not an intrinsic component of the nucleosome core particle, linker histone H1 directly interacts with it in a monomeric form. Histone H1 binds nucleosomes near the exit/entry sites of linker DNA, determines nucleosome repeat length and stabilizes higher-order organization of nucleosomes into the ∼30 nm chromatin fiber. In comparison to core histones, histone H1 is less well conserved through evolution. Furthermore, histone H1 composition in metazoans is generally complex with most species containing multiple variants that play redundant as well as specific functions. In this regard, a characteristic feature is the presence of specific H1 variants that replace somatic H1s in the germline and during early embryogenesis. In this review, we summarize our current knowledge about their structural and functional properties.

Tug of war: adding and removing histone lysine methylation in Arabidopsis.

PubMed

Xiao, Jun; Lee, Un-Sa; Wagner, Doris

2016-12-01

Histone lysine methylation plays a fundamental role in the epigenetic regulation of gene expression in multicellular eukaryotes, including plants. It shapes plant developmental and growth programs as well as responses to the environment. The methylation status of certain amino-acids, in particular of the histone 3 (H3) lysine tails, is dynamically controlled by opposite acting histone methyltransferase 'writers' and histone demethylase 'erasers'. The methylation status is interpreted by a third set of proteins, the histone modification 'readers', which specifically bind to a methylated amino-acid on the H3 tail. Histone methylation writers, readers, and erasers themselves are regulated by intrinsic or extrinsic stimuli; this forms a feedback loop that contributes to development and environmental adaptation in Arabidopsis and other plants. Recent studies have expanded our knowledge regarding the biological roles and dynamic regulation of histone methylation. In this review, we will discuss recent advances in understanding the regulation and roles of histone methylation in plants and animals. Copyright © 2016 Elsevier Ltd. All rights reserved.

Probing the interaction between the histone methyltransferase/deacetylase subunit RBBP4/7 and the transcription factor BCL11A in epigenetic complexes.

PubMed

Moody, Rebecca Reed; Lo, Miao-Chia; Meagher, Jennifer L; Lin, Chang-Ching; Stevers, Nicholas O; Tinsley, Samantha L; Jung, Inkyung; Matvekas, Aleksas; Stuckey, Jeanne A; Sun, Duxin

2018-02-09

The transcription factor BCL11A has recently been reported to be a driving force in triple-negative breast cancer (TNBC), contributing to the maintenance of a chemoresistant breast cancer stem cell (BCSC) population. Although BCL11A was shown to suppress γ-globin and p21 and to induce MDM2 expression in the hematopoietic system, its downstream targets in TNBC are still unclear. For its role in transcriptional repression, BCL11A was found to interact with several corepressor complexes; however, the mechanisms underlying these interactions remain unknown. Here, we reveal that BCL11A interacts with histone methyltransferase (PRC2) and histone deacetylase (NuRD and SIN3A) complexes through their common subunit, RBBP4/7. In fluorescence polarization assays, we show that BCL11A competes with histone H3 for binding to the negatively charged top face of RBBP4. To define that interaction, we solved the crystal structure of RBBP4 in complex with an N-terminal peptide of BCL11A (residues 2-16, BCL11A(2-16)). The crystal structure identifies novel interactions between BCL11A and the side of the β-propeller of RBBP4 that are not seen with histone H3. We next show that BCL11A(2-16) pulls down RBBP4, RBBP7, and other components of PRC2, NuRD, and SIN3A from the cell lysate of the TNBC cell line SUM149. Furthermore, we demonstrate the therapeutic potential of targeting the RBBP4-BCL11A binding by showing that a BCL11A peptide can decrease aldehyde dehydrogenase-positive BCSCs and mammosphere formation capacity in SUM149. Together, our findings have uncovered a previously unidentified mechanism that BCL11A may use to recruit epigenetic complexes to regulate transcription and promote tumorigenesis. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Histone deacetylases play a major role in the transcriptional regulation of the Plasmodium falciparum life cycle.

PubMed

Chaal, Balbir K; Gupta, Archna P; Wastuwidyaningtyas, Brigitta D; Luah, Yen-Hoon; Bozdech, Zbynek

2010-01-22

The apparent paucity of molecular factors of transcriptional control in the genomes of Plasmodium parasites raises many questions about the mechanisms of life cycle regulation in these malaria parasites. Epigenetic regulation has been suggested to play a major role in the stage specific gene expression during the Plasmodium life cycle. To address some of these questions, we analyzed global transcriptional responses of Plasmodium falciparum to a potent inhibitor of histone deacetylase activities (HDAC). The inhibitor apicidin induced profound transcriptional changes in multiple stages of the P. falciparum intraerythrocytic developmental cycle (IDC) that were characterized by rapid activation and repression of a large percentage of the genome. A major component of this response was induction of genes that are otherwise suppressed during that particular stage of the IDC or specific for the exo-erythrocytic stages. In the schizont stage, apicidin induced hyperacetylation of histone lysine residues H3K9, H4K8 and the tetra-acetyl H4 (H4Ac4) and demethylation of H3K4me3. Interestingly, we observed overlapping patterns of chromosomal distributions between H4K8Ac and H3K4me3 and between H3K9Ac and H4Ac4. There was a significant but partial association between the apicidin-induced gene expression and histone modifications, which included a number of stage specific transcription factors. Taken together, inhibition of HDAC activities leads to dramatic de-regulation of the IDC transcriptional cascade, which is a result of both disruption of histone modifications and up-regulation of stage specific transcription factors. These findings suggest an important role of histone modification and chromatin remodeling in transcriptional regulation of the Plasmodium life cycle. This also emphasizes the potential of P. falciparum HDACs as drug targets for malaria chemotherapy.

Replication-coupled chromatin assembly of newly synthesized histones: distinct functions for the histone tail domains.

PubMed

Ejlassi-Lassallette, Aïda; Thiriet, Christophe

2012-02-01

The maintenance of the genome during replication requires the assembly of nucleosomes with newly synthesized histones. Achieving the deposition of newly synthesized histones in chromatin implies their transport from the cytoplasm to the nucleus at the replication sites. Several lines of evidence have revealed critical functions of the histone tail domains in these conserved cellular processes. In this review, we discuss the role of the amino termini of the nucleosome building blocks, H2A/H2B and H3/H4, in different model systems. The experimental data showed that H2A/H2B tails and H3/H4 tails display distinct functions in nuclear import and chromatin assembly. Furthermore, we describe recent studies exploiting the unique properties of the slime mold, Physarum polycephalum , that have advanced understanding of the function of the highly conserved replication-dependent diacetylation of H4.

Combinatorial modification of human histone H4 quantitated by two-dimensional liquid chromatography coupled with top down mass spectrometry.

PubMed

Pesavento, James J; Bullock, Courtney R; LeDuc, Richard D; Mizzen, Craig A; Kelleher, Neil L

2008-05-30

Quantitative proteomics has focused heavily on correlating protein abundances, ratios, and dynamics by developing methods that are protein expression-centric (e.g. isotope coded affinity tag, isobaric tag for relative and absolute quantification, etc.). These methods effectively detect changes in protein abundance but fail to provide a comprehensive perspective of the diversity of proteins such as histones, which are regulated by post-translational modifications. Here, we report the characterization of modified forms of HeLa cell histone H4 with a dynamic range >10(4) using a strictly Top Down mass spectrometric approach coupled with two dimensions of liquid chromatography. This enhanced dynamic range enabled the precise characterization and quantitation of 42 forms uniquely modified by combinations of methylation and acetylation, including those with trimethylated Lys-20, monomethylated Arg-3, and the novel dimethylated Arg-3 (each <1% of all H4 forms). Quantitative analyses revealed distinct trends in acetylation site occupancy depending on Lys-20 methylation state. Because both modifications are dynamically regulated through the cell cycle, we simultaneously investigated acetylation and methylation kinetics through three cell cycle phases and used these data to statistically assess the robustness of our quantitative analysis. This work represents the most comprehensive analysis of histone H4 forms present in human cells reported to date.

[Occupational and non-occupational factors influencing health state of small and medium business workers].

PubMed

Fasikov, R M; Khuzhakhmetova, I B; Stepanov, E G

2010-01-01

Complex study of work conditions and health parameters of workers engaged into small and medium business proved that preserved and better health of these workers, prevention of occupational and occupationally mediated diseases necessitate federal and regional complex system of measures including legal basis, database on work conditions and their influence on small and medium business workers' health, occupational medicine training for employers and employees, more active involvement of medical institutioins into screening for occupational diseases.

The impact of occupational stress factors on temporary work disability related to arterial hypertension and its complications.

PubMed

Lazaridis, Konstantinos; Jovanović, Jovica; Jovanović, Jovana; Šarac, Ivana; Jovanović, Stefan

2017-06-01

To determine which specific groups of occupational stress factors influence the duration of temporary work disability related to arterial hypertension and joint complications/co-morbidities. Workers (n = 1398; 1009 in the exposed group, 389 in the control group) with arterial hypertension who worked at one workplace for a minimum of 10 years were divided into 10 subgroups, depending on the presence of joint complications/co-morbidities. The intensity of seven groups of occupational stress factors, the total score of Occupational Stress Index (OSI) and the average number of lost working days during 1 year were analysed. The number of lost working days due to arterial hypertension and joint complications/co-morbidities was significantly higher in the exposed group. In all subgroups of the exposed group there was a high correlation between the number of lost working days and the total OSI score. Specific occupational stress factors were associated with specific complications: High Demands with chronic myocardial infarction, Strictness with cerebral haemorrhage, Conflict/Uncertainty with cerebral infarction, Extrinsic Time Pressure with acute myocardial infarction, and Avoidance/Symbolic Aversiveness with non-insulin-dependent diabetes. There are specific groups of occupational stress factors which can influence the duration of work disability associated with certain complications and co-morbidities of arterial hypertension.

Involvement of histone methylation in macrophage apoptosis and unstable plaque formation in methionine-induced hyperhomocysteinemic ApoE-/- mice.

PubMed

Cong, Guangzhi; Yan, Ru; Huang, Hui; Wang, Kai; Yan, Ning; Jin, Ping; Zhang, Na; Hou, Jianjun; Chen, Dapeng; Jia, Shaobin

2017-03-15

Hyperhomocysteinemia (Hhcy) is an independent risk factor of atherosclerosis and promotes unstable plaque formation. Epigenetic mechanisms play an important role in the pathogenesis of atherosclerosis induced by Hhcy. However, the exact mechanism is still undefined. Lesional apoptotic cells and necrotic core formation contribute greatly to the progression of plaque. The present study sought to determine whether modification of histone methylation is involved in macrophage apoptosis and unstable plaque formation in the condition of Hhcy. The unstable plaque formation, lesional apoptotic cells and status of histone methylation were monitored in the aortas of Hhcy ApoE -/- mice induced by a high-methionine (HM) diet for 20weeks. Involvement of histone methylation in macrophage apoptosis and foam cell formation were assessed in macrophage Raw 264.7 cells after being challenged with homocysteine alone or in combination with the histone methylation inhibitor BIX 01294. The unstable plaque formation and lesion apoptotic cells are increased in ApoE -/ - mice supplemented with high-methionine (HM), accompanied with a decreased expression of histone H3 lysine 9 dimethylation. Hhcy increases the apoptosis of macrophages and inhibits the histone H3 lysine 9 dimethylation, as well as the expression of histone methyltransferase G9a in vitro. Inhibition of histone methylation by BIX01294 enhances macrophage apoptosis and foam cell formation in vitro. Our data suggest that Hhcy promotes the progression of atherosclerosis via macrophage apoptosis. Histone methylation might be involved in macrophage apoptosis and unstable plaque formation in methionine induced hyperhomocysteinemic ApoE -/- mice. Copyright © 2017 Elsevier Inc. All rights reserved.

Systemic sclerosis and occupational risk factors: role of solvents and cleaning products.

PubMed

Maître, Anne; Hours, Martine; Bonneterre, Vincent; Arnaud, Joëlle; Arslan, Marie Tülin; Carpentier, Patrick; Bergeret, Alain; de Gaudemaris, Régis

2004-12-01

To analyze occupational and non-occupational exposure factors suspected of being associated with scleroderma (SSc), with a view to inculpating or excluding certain potentially toxic substances (e.g., solvents), thereby contributing to the recognition of such toxins in the field of occupational health. The study comprised 10 men and 83 women diagnosed with SSc between 1995 and 1999 (American College of Rheumatology criteria) and early SSc, and 206 age and sex matched controls. The SSc registry is all-inclusive in the French administrative departments of Isere and Savoie so controls were randomly selected from the general population (using telephone directories) in these departments to ensure full representation. Exposure factors were analyzed for each subject by a personal questionnaire, and an individual evaluation was carried out by an industrial expert. Data were analyzed by conditional logistical regression adjusting for educational level. Construction workers were at significantly higher risk of contracting SSc; odds ratio (OR) = 4.01 (95% confidence interval 1.14-14.09). Analysis by industrial experts identified exposure to certain toxic substances regularly used by these same workers as risk factors for SSc: cleaning products: OR = 1.66 (0.90-3.08) (both sexes) and OR = 1.71 (0.92-3.20) (women only); solvents: OR = 3.23 (1.58-6.63) (both sexes) and OR = 2.80 (1.28-6.11) (women only); synthetic adhesives: OR 25.36 (1.36-472.28) (on 3 exposed cases). Exposure to either cleaning products or solvents emerged as a risk factor for SSc. Exposure factors should be characterized and results of all studies compared to implement appropriate preventive measures in relevant workplaces.

Neutrophil Extracellular Trap-Related Extracellular Histones Cause Vascular Necrosis in Severe GN.

PubMed

Kumar, Santhosh V R; Kulkarni, Onkar P; Mulay, Shrikant R; Darisipudi, Murthy N; Romoli, Simone; Thomasova, Dana; Scherbaum, Christina R; Hohenstein, Bernd; Hugo, Christian; Müller, Susanna; Liapis, Helen; Anders, Hans-Joachim

2015-10-01

Severe GN involves local neutrophil extracellular trap (NET) formation. We hypothesized a local cytotoxic effect of NET-related histone release in necrotizing GN. In vitro, histones from calf thymus or histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells in a dose-dependent manner. Histone-neutralizing agents such as antihistone IgG, activated protein C, or heparin prevented this effect. Histone toxicity on glomeruli ex vivo was Toll-like receptor 2/4 dependent, and lack of TLR2/4 attenuated histone-induced renal thrombotic microangiopathy and glomerular necrosis in mice. Anti-glomerular basement membrane GN involved NET formation and vascular necrosis, whereas blocking NET formation by peptidylarginine inhibition or preemptive anti-histone IgG injection significantly reduced all aspects of GN (i.e., vascular necrosis, podocyte loss, albuminuria, cytokine induction, recruitment or activation of glomerular leukocytes, and glomerular crescent formation). To evaluate histones as a therapeutic target, mice with established GN were treated with three different histone-neutralizing agents. Anti-histone IgG, recombinant activated protein C, and heparin were equally effective in abrogating severe GN, whereas combination therapy had no additive effects. Together, these results indicate that NET-related histone release during GN elicits cytotoxic and immunostimulatory effects. Furthermore, neutralizing extracellular histones is still therapeutic when initiated in established GN. Copyright © 2015 by the American Society of Nephrology.

Structural and Functional Coordination of DNA and Histone Methylation

PubMed Central

Cheng, Xiaodong

2014-01-01

One of the most fundamental questions in the control of gene expression in mammals is how epigenetic methylation patterns of DNA and histones are established, erased, and recognized. This central process in controlling gene expression includes coordinated covalent modifications of DNA and its associated histones. This article focuses on structural aspects of enzymatic activities of histone (arginine and lysine) methylation and demethylation and functional links between the methylation status of the DNA and histones. An interconnected network of methyltransferases, demethylases, and accessory proteins is responsible for changing or maintaining the modification status of specific regions of chromatin. PMID:25085914

Adolescent alcohol exposure alters lysine demethylase 1 (LSD1) expression and histone methylation in the amygdala during adulthood.

PubMed

Kyzar, Evan J; Zhang, Huaibo; Sakharkar, Amul J; Pandey, Subhash C

2017-09-01

Alcohol exposure in adolescence is an important risk factor for the development of alcoholism in adulthood. Epigenetic processes are implicated in the persistence of adolescent alcohol exposure-related changes, specifically in the amygdala. We investigated the role of histone methylation mechanisms in the persistent effects of adolescent intermittent ethanol (AIE) exposure in adulthood. Adolescent rats were exposed to 2 g/kg ethanol (2 days on/off) or intermittent n-saline (AIS) during postnatal days (PND) 28-41 and used for behavioral and epigenetic studies. We found that AIE exposure caused a long-lasting decrease in mRNA and protein levels of lysine demethylase 1(Lsd1) and mRNA levels of Lsd1 + 8a (a neuron-specific splice variant) in specific amygdaloid structures compared with AIS-exposed rats when measured at adulthood. Interestingly, AIE increased histone H3 lysine 9 dimethylation (H3K9me2) levels in the central nucleus of the amygdala (CeA) and medial nucleus of the amygdala (MeA) in adulthood without producing any change in H3K4me2 protein levels. Acute ethanol challenge (2 g/kg) in adulthood attenuated anxiety-like behaviors and the decrease in Lsd1 + 8a mRNA levels in the amygdala induced by AIE. AIE caused an increase in H3K9me2 occupancy at the brain-derived neurotrophic factor exon IV promoter in the amygdala that returned to baseline after acute ethanol challenge in adulthood. These results indicate that AIE specifically modulates epizymes involved in H3K9 dimethylation in the amygdala in adulthood, which are possibly responsible for AIE-induced chromatin remodeling and adult psychopathology such as anxiety. © Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

The N-terminus of histone H2B, but not that of histone H3 or its phosphorylation, is essential for chromosome condensation

PubMed Central

de la Barre, Anne-Elisabeth; Angelov, Dimitri; Molla, Annie; Dimitrov, Stefan

2001-01-01

We have studied the role of individual histone N-termini and the phosphorylation of histone H3 in chromosome condensation. Nucleosomes, reconstituted with histone octamers containing different combinations of recombinant full-length and tailless histones, were used as competitors for chromosome assembly in Xenopus egg extracts. Nucleosomes reconstituted with intact octamers inhibited chromosome condensation as efficiently as the native ones, while tailless nucleosomes were unable to affect this process. Importantly, the addition to the extract of particles containing only intact histone H2B strongly interfered with chromosome formation while such an effect was not observed with particles lacking the N-terminal tail of H2B. This demonstrates that the inhibition effect observed in the presence of competitor nucleosomes is mainly due to the N-terminus of this histone, which, therefore, is essential for chromosome condensation. Nucleosomes in which all histones but H3 were tailless did not impede chromosome formation. In addition, when competitor nucleosome particles were reconstituted with full-length H2A, H2B and H4 and histone H3 mutated at the phosphorylable serine 10 or serine 28, their inhibiting efficiency was identical to that of the native particles. Hence, the tail of H3, whether intact or phosphorylated, is not important for chromosome condensation. A novel hypothesis, termed ‘the ready production label’ was suggested to explain the role of histone H3 phosphorylation during cell division. PMID:11707409

The histone acetyltransferase component TRRAP is targeted for destruction during the cell cycle.

PubMed

Ichim, G; Mola, M; Finkbeiner, M G; Cros, M-P; Herceg, Z; Hernandez-Vargas, H

2014-01-09

Chromosomes are dynamic structures that must be reversibly condensed and unfolded to accommodate mitotic division and chromosome segregation. Histone modifications are involved in the striking chromatin reconfiguration taking place during mitosis. However, the mechanisms that regulate activity and function of histone-modifying factors as cells enter and exit mitosis are poorly understood. Here, we show that the anaphase-promoting complex or cyclosome (APC/C) is involved in the mitotic turnover of TRRAP (TRansformation/tRanscription domain-Associated Protein), a common component of histone acetyltransferase (HAT) complexes, and that the pre-mitotic degradation of TRRAP is mediated by the APC/C ubiquitin ligase activators Cdc20 and Cdh1. Ectopic expression of both Cdh1 and Cdc20 reduced the levels of coexpressed TRRAP protein and induced its ubiquitination. TRRAP overexpression or stabilization induces multiple mitotic defects, including lagging chromosomes, chromosome bridges and multipolar spindles. In addition, lack of sister chromatid cohesion and impaired chromosome condensation were found after TRRAP overexpression or stabilization. By using a truncated form of TRRAP, we show that mitotic delay is associated with a global histone H4 hyperacetylation induced by TRRAP overexpression. These results demonstrate that the chromatin modifier TRRAP is targeted for destruction in a cell cycle-dependent fashion. They also suggest that degradation of TRRAP by the APC/C is necessary for a proper condensation of chromatin and proper chromosome segregation. Chromatin compaction mediated by histone modifiers may represent a fundamental arm for APC/C orchestration of the mitotic machinery.

Significance of the DNA-Histone Complex Level as a Predictor of Major Adverse Cardiovascular Events in Hemodialysis Patients: The Effect of Uremic Toxin on DNA-Histone Complex Formation.

PubMed

Jeong, Jong Cheol; Kim, Ji-Eun; Gu, Ja-Yoon; Yoo, Hyun Ju; Ryu, Ji Won; Kim, Dong Ki; Joo, Kwon Wook; Kim, Hyun Kyung

2016-01-01

Neutrophils can release the DNA-histone complex into circulation following exposure to inflammatory stimuli. This prospective study investigated whether the DNA-histone complex and other biomarkers could predict major cardiovascular adverse events (MACEs) in hemodialysis (HD) patients. The levels of circulating DNA-histone complexes, cell-free DNA, interleukin (IL)-6, and neutrophil elastase were measured in 60 HD patients and 28 healthy controls. MACE was assessed at 24 months. Uremic toxin-induced neutrophil released contents were measured in vitro. Compared with controls, HD patients showed higher levels of DNA-histone complexes and IL-6. The DNA-histone complex level was inversely associated with the Kt/V. In a multivariable Cox analysis, the high level of DNA-histone complexes was a significant independent predictor of MACE. The uremic toxins induced DNA-histone complex formation in normal neutrophils in vitro. The DNA-histone complex is a potentially useful marker to predict MACE in HD patients. Uremic toxins induced DNA-histone complex formation in vitro. © 2015 S. Karger AG, Basel.

Boric acid-dependent decrease in regulatory histone H3 acetylation is not mutagenic in yeast.

PubMed

Pointer, Benjamin R; Schmidt, Martin

2016-07-01

Candida albicans is a dimorphic yeast commonly found on human mucosal membranes that switches from yeast to hyphal morphology in response to environmental factors. The change to hyphal growth requires histone H3 modifications by the yeast-specific histone acetyltransferase Rtt109. In addition to its role in morphogenesis, Rtt109-dependent acetylation of histone H3 lysine residues 9 and 56 has regulatory functions during DNA replication and repair. Boric acid (BA) is a broad-spectrum agent that specifically inhibits C. albicans hyphal growth, locking the fungus in its harmless commensal yeast state. The present study characterizes the effect of BA on C. albicans histone acetylation in respect to specificity, time-course and significance. We demonstrate that sublethal concentrations of BA reduce H3K9/H3K56 acetylation, both on a basal level and in response to genotoxic stress. Acetylation at other selected histone sites were not affected by BA. qRT-PCR expression analysis of the DNA repair gene Rad51 indicated no elevated level of genotoxic stress during BA exposure. A forward-mutation analysis demonstrated the BA does not increase spontaneous or induced mutations. The findings suggest that DNA repair remains effective even when histone H3 acetylation decreases and dispels the notion that BA treatment impairs genome integrity in yeast. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A histone H3K9M mutation traps histone methyltransferase Clr4 to prevent heterochromatin spreading

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shan, Chun-Min; Wang, Jiyong; Xu, Ke

2016-09-20

Histone lysine-to-methionine (K-to-M) mutations are associated with multiple cancers, and they function in a dominant fashion to block the methylation of corresponding lysines on wild type histones. However, their mechanisms of function are controversial. Here we show that in fission yeast, introducing the K9M mutation into one of the three histone H3 genes dominantly blocks H3K9 methylation on wild type H3 across the genome. In addition, H3K9M enhances the interaction of histone H3 tail with the H3K9 methyltransferase Clr4 in a SAM (S-adenosyl-methionine)-dependent manner, and Clr4 is trapped at nucleation sites to prevent its spreading and the formation of largemore » heterochromatin domains. We further determined the crystal structure of an H3K9M peptide in complex with human H3K9 methyltransferase G9a and SAM, which reveales that the methionine side chain had enhanced van der Waals interactions with G9a. Therefore, our results provide a detailed mechanism by which H3K9M regulates H3K9 methylation.« less

[Risk, cause and disease in the occupational environment. Neurologic risk factors].

PubMed

Maqueda-Blasco, J

In this paper we study the epidemiological criteria and those of etiological investigation which should be considered when analysing and investigating problems with health due to exposure to occupational hazards, with special attention to neurological damage due to chemical or physical contamination or to the ergonometric requirements of the task. We define the part played by occupational hazards in causing disease both professional and related to other occupations. The different preventive models used in the history of prevention of professional hazards are analysed. Particular attention is paid to the so-called socio-technical model which considers illness as dysfunction of the relation man/work. The neurological risk factors are analysed separately; therefore we emphasize the different neurotoxic chemicals, physical and ergonomic agents (the latter may be considered a pandemic in the workplace), and we establish the relationships with the main clinical and functional disorders of the central and peripheral nervous systems and the musculoskeletal system.

A comparison of the relationships between psychosocial factors, occupational strain, and work ability among 4 ethnic teacher groups in China.

PubMed

Lian, Yulong; Xiao, Jing; Zhang, Chen; Guan, Suzhen; Li, Fuye; Ge, Hua; Liu, Jiwen

2016-01-01

The present study compared the level of occupational strain and work ability among Han, Hui, Uygur, Hui, and Kazakh teachers, and explored ethnic differences based on the associations of psychosocial factors at work, occupational strain, and work ability. A cross-sectional survey was conducted among 2,941 teachers in primary and secondary schools in Xinjiang Province, China. Psychosocial factors, occupational strain, and work ability were measured using the Occupation Stress Inventory-Revised Edition (OSI-R) and Work Ability Index. Han and Hui teachers experienced reduced work ability compared with Uygur and Kazakh teachers, and this finding was caused, in part, by exposure to psychosocial factors at work. The vocational and psychological strains caused by these factors play an important role in reduced work ability among all ethnic teacher groups. The findings indicate the importance of taking action to reduce occupational strain for promoting teachers' work ability in multiethnic workplaces.

Organizational factors related to occupational accidents in construction.

PubMed

Filho, J M Jackson; Fonseca, E D; Lima, F P A; Duarte, F J C M

2012-01-01

The purpose of this paper is to understand the influence of organizational factors on occupational accident causation. A field study was undertaken and focused on the phase of concreting the floors of a residential block in a building project in Brazil. The methodological approach was based on the analysis of carpenters' work practices and of the workers' accounts of minor falls. Observations were noted on work practices over this stage. Furthermore, interviews were conducted with the workers hired by the subcontractors and with professionals working for the main contractor. The results show that falls were related to the introduction of new building technology and its use by the workforce. The production planning and organization of activities by the subcontracted firms also led to temporary demands that were additional determining factors for falls on site. The work analysis reveals the need to consider organizational factors in prevention practices.

Occupational Risk Factors and Asthma among Health Care Professionals

PubMed Central

Delclos, George L.; Gimeno, David; Arif, Ahmed A.; Burau, Keith D.; Carson, Arch; Lusk, Christine; Stock, Thomas; Symanski, Elaine; Whitehead, Lawrence W.; Zock, Jan-Paul; Benavides, Fernando G.; Antó, Josep M.

2007-01-01

Rationale: Recent U.S. data suggest an increased risk of work-related asthma among health care workers, yet only a few specific determinants have been elucidated. Objectives: To evaluate associations of asthma prevalence with occupational exposures in a cross-sectional survey of health care professionals. Methods: A detailed questionnaire was mailed to a random sample (n = 5,600) of all Texas physicians, nurses, respiratory therapists, and occupational therapists with active licenses in 2003. Information on asthma symptoms and nonoccupational asthma risk factors obtained from the questionnaire was linked to occupational exposures derived through an industry-specific job-exposure matrix. Measurements: There were two a priori defined outcomes: (1) physician-diagnosed asthma with onset after entry into health care (“reported asthma”) and (2) “bronchial hyperresponsiveness–related symptoms,” defined through an 8-item symptom-based predictor. Main Results: Overall response rate was 66%. The final study population consisted of 862 physicians, 941 nurses, 968 occupational therapists, and 879 respiratory therapists (n = 3,650). Reported asthma was associated with medical instrument cleaning (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.34–3.67), general cleaning (OR, 2.02; 95% CI, 1.20–3.40), use of powdered latex gloves between 1992 and 2000 (OR, 2.17; 95% CI, 1.27–3.73), and administration of aerosolized medications (OR, 1.72; 95% CI, 1.05–2.83). The risk associated with latex glove use was not apparent after 2000. Bronchial hyperresponsiveness–related symptoms were associated with general cleaning (OR, 1.63; 95% CI, 1.21–2.19), aerosolized medication administration (OR, 1.40; 95% CI, 1.06–1.84), use of adhesives on patients (OR, 1.65; 95% CI, 1.22–2.24), and exposure to a chemical spill (OR, 2.02; 95% CI, 1.28–3.21). Conclusions: The contribution of occupational exposures to asthma in health care professionals is not trivial

Organizing pneumonia and occupational and environmental risk factors: a case-control study.

PubMed

Jobard, Stéphanie; Chaigne, Benjamin; Marchand-Adam, Sylvain; Lasfargues, Gérard; Diot, Elisabeth

2017-11-01

A single-center case-control study was carried out to investigate the relationship between occupational and environmental exposure and organizing pneumonia (OP). Thirty-seven cases of OP, including 25 cases of cryptogenic OP, and 111 controls were included. Occupational exposure was assessed retrospectively by an industrial hygienist and an occupational physician, through semi-quantitative estimates of exposure. An exposure score was calculated for each subject, based on probability, intensity, daily frequency, and duration of exposure for each period of employment. The final cumulative exposure score was obtained by summing exposure scores for all periods of employment. Significant associations with all-cause OP were observed for exposure to tetrachloroethylene (OR 13.33, CI 95% 1.44-123.5) and silica (OR 6.61, CI 95% 1.16-37.71). A significant association with cryptogenic OP was observed only for tetrachloroethylene (OR 31.6, CI 95% 1.64-610.8). No associations were found for environmental exposure. Despite its low statistical power, this work suggests that occupational risk factors could be involved in OP.

Histone variant innovation in a rapidly evolving chordate lineage.

PubMed

Moosmann, Alexandra; Campsteijn, Coen; Jansen, Pascal Wtc; Nasrallah, Carole; Raasholm, Martina; Stunnenberg, Henk G; Thompson, Eric M

2011-07-15

Histone variants alter the composition of nucleosomes and play crucial roles in transcription, chromosome segregation, DNA repair, and sperm compaction. Modification of metazoan histone variant lineages occurs on a background of genome architecture that shows global similarities from sponges to vertebrates, but the urochordate, Oikopleura dioica, a member of the sister group to vertebrates, exhibits profound modification of this ancestral architecture. We show that a histone complement of 47 gene loci encodes 31 histone variants, grouped in distinct sets of developmental expression profiles throughout the life cycle. A particularly diverse array of 15 male-specific histone variants was uncovered, including a testes-specific H4t, the first metazoan H4 sequence variant reported. Universal histone variants H3.3, CenH3, and H2A.Z are present but O. dioica lacks homologs of macroH2A and H2AX. The genome encodes many H2A and H2B variants and the repertoire of H2A.Z isoforms is expanded through alternative splicing, incrementally regulating the number of acetylatable lysine residues in the functionally important N-terminal "charge patch". Mass spectrometry identified 40 acetylation, methylation and ubiquitylation posttranslational modifications (PTMs) and showed that hallmark PTMs of "active" and "repressive" chromatin were present in O. dioica. No obvious reduction in silent heterochromatic marks was observed despite high gene density in this extraordinarily compacted chordate genome. These results show that histone gene complements and their organization differ considerably even over modest phylogenetic distances. Substantial innovation among all core and linker histone variants has evolved in concert with adaptation of specific life history traits in this rapidly evolving chordate lineage.

Identification of histone modifications in biomedical text for supporting epigenomic research

PubMed Central

Kolářik, Corinna; Klinger, Roman; Hofmann-Apitius, Martin

2009-01-01

Background Posttranslational modifications of histones influence the structure of chromatine and in such a way take part in the regulation of gene expression. Certain histone modification patterns, distributed over the genome, are connected to cell as well as tissue differentiation and to the adaption of organisms to their environment. Abnormal changes instead influence the development of disease states like cancer. The regulation mechanisms for modifying histones and its functionalities are the subject of epigenomics investigation and are still not completely understood. Text provides a rich resource of knowledge on epigenomics and modifications of histones in particular. It contains information about experimental studies, the conditions used, and results. To our knowledge, no approach has been published so far for identifying histone modifications in text. Results We have developed an approach for identifying histone modifications in biomedical literature with Conditional Random Fields (CRF) and for resolving the recognized histone modification term variants by term standardization. For the term identification F1 measures of 0.84 by 10-fold cross-validation on the training corpus and 0.81 on an independent test corpus have been obtained. The standardization enabled the correct transformation of 96% of the terms from training and 98% from test the corpus. Due to the lack of terminologies exhaustively covering specific histone modification types, we developed a histone modification term hierarchy for use in a semantic text retrieval system. Conclusion The developed approach highly improves the retrieval of articles describing histone modifications. Since text contains context information about performed studies and experiments, the identification of histone modifications is the basis for supporting literature-based knowledge discovery and hypothesis generation to accelerate epigenomic research. PMID:19208128

Identification of histone modifications in biomedical text for supporting epigenomic research.

PubMed

Kolárik, Corinna; Klinger, Roman; Hofmann-Apitius, Martin

2009-01-30

Posttranslational modifications of histones influence the structure of chromatine and in such a way take part in the regulation of gene expression. Certain histone modification patterns, distributed over the genome, are connected to cell as well as tissue differentiation and to the adaption of organisms to their environment. Abnormal changes instead influence the development of disease states like cancer. The regulation mechanisms for modifying histones and its functionalities are the subject of epigenomics investigation and are still not completely understood. Text provides a rich resource of knowledge on epigenomics and modifications of histones in particular. It contains information about experimental studies, the conditions used, and results. To our knowledge, no approach has been published so far for identifying histone modifications in text. We have developed an approach for identifying histone modifications in biomedical literature with Conditional Random Fields (CRF) and for resolving the recognized histone modification term variants by term standardization. For the term identification F1 measures of 0.84 by 10-fold cross-validation on the training corpus and 0.81 on an independent test corpus have been obtained. The standardization enabled the correct transformation of 96% of the terms from training and 98% from test the corpus. Due to the lack of terminologies exhaustively covering specific histone modification types, we developed a histone modification term hierarchy for use in a semantic text retrieval system. The developed approach highly improves the retrieval of articles describing histone modifications. Since text contains context information about performed studies and experiments, the identification of histone modifications is the basis for supporting literature-based knowledge discovery and hypothesis generation to accelerate epigenomic research.

Histone lysine methylation: critical regulator of memory and behavior.

PubMed

Jarome, Timothy J; Lubin, Farah D

2013-01-01

Histone lysine methylation is a well-established transcriptional mechanism for the regulation of gene expression changes in eukaryotic cells and is now believed to function in neurons of the central nervous system to mediate the process of memory formation and behavior. In mature neurons, methylation of histone proteins can serve to both activate and repress gene transcription. This is in stark contrast to other epigenetic modifications, including histone acetylation and DNA methylation, which have largely been associated with one transcriptional state in the brain. In this review, we discuss the evidence for histone methylation mechanisms in the coordination of complex cognitive processes such as long-term memory formation and storage. In addition, we address the current literature highlighting the role of histone methylation in intellectual disability, addiction, schizophrenia, autism, depression, and neurodegeneration. Further, we discuss histone methylation within the context of other epigenetic modifications and the potential advantages of exploring this newly identified mechanism of cognition, emphasizing the possibility that this molecular process may provide an alternative locus for intervention in long-term psychopathologies that cannot be clearly linked to genes or environment alone.

Asymmetric binding of histone H1 stabilizes MMTV nucleosomes and the interaction of progesterone receptor with the exposed HRE.

PubMed

Vicent, Guillermo P; Meliá, María J; Beato, Miguel

2002-11-29

Packaging of mouse mammary tumor virus (MMTV) promoter sequences in nucleosomes modulates access of DNA binding proteins and influences the interaction among DNA bound transcription factors. Here we analyze the binding of histone H1 to MMTV mononucleosomes assembled with recombinant histones and study its influence on nucleosome structure and stability as well as on progesterone receptor (PR) binding to the hormone responsive elements (HREs). The MMTV nucleosomes can be separated into three main populations, two of which exhibited precise translational positioning. Histone H1 bound preferentially to the 5' distal nucleosomal DNA protecting additional 27-28 nt from digestion by micrococcal nuclease. Binding of histone H1 was unaffected by prior crosslinking of protein and DNA in nucleosomes with formaldehyde. Neither the translational nor the rotational nucleosome positioning was altered by histone H1 binding, but the nucleosomes were stabilized as judged by the kinetics of nuclease cleavage. Unexpectedly, binding of recombinant PR to the exposed distal HRE-I in nucleosomes was enhanced in the presence of histone H1, as demonstrated by band shift and footprinting experiments. This enhanced PR affinity may contribute to the reported positive effect of histone H1 on the hormonal activation of MMTV reporter genes.

Modeling of Individual and Organizational Factors Affecting Traumatic Occupational Injuries Based on the Structural Equation Modeling: A Case Study in Large Construction Industries.

PubMed

Mohammadfam, Iraj; Soltanzadeh, Ahmad; Moghimbeigi, Abbas; Akbarzadeh, Mehdi

2016-09-01

Individual and organizational factors are the factors influencing traumatic occupational injuries. The aim of the present study was the short path analysis of the severity of occupational injuries based on individual and organizational factors. The present cross-sectional analytical study was implemented on traumatic occupational injuries within a ten-year timeframe in 13 large Iranian construction industries. Modeling and data analysis were done using the structural equation modeling (SEM) approach and the IBM SPSS AMOS statistical software version 22.0, respectively. The mean age and working experience of the injured workers were 28.03 ± 5.33 and 4.53 ± 3.82 years, respectively. The portions of construction and installation activities of traumatic occupational injuries were 64.4% and 18.1%, respectively. The SEM findings showed that the individual, organizational and accident type factors significantly were considered as effective factors on occupational injuries' severity (P < 0.05). Path analysis of occupational injuries based on the SEM reveals that individual and organizational factors and their indicator variables are very influential on the severity of traumatic occupational injuries. So, these should be considered to reduce occupational accidents' severity in large construction industries.

Computational Identification of Diverse Mechanisms Underlying Transcription Factor-DNA Occupancy

PubMed Central

Cheng, Qiong; Kazemian, Majid; Pham, Hannah; Blatti, Charles; Celniker, Susan E.; Wolfe, Scot A.; Brodsky, Michael H.; Sinha, Saurabh

2013-01-01

ChIP-based genome-wide assays of transcription factor (TF) occupancy have emerged as a powerful, high-throughput method to understand transcriptional regulation, especially on a global scale. This has led to great interest in the underlying biochemical mechanisms that direct TF-DNA binding, with the ultimate goal of computationally predicting a TF's occupancy profile in any cellular condition. In this study, we examined the influence of various potential determinants of TF-DNA binding on a much larger scale than previously undertaken. We used a thermodynamics-based model of TF-DNA binding, called “STAP,” to analyze 45 TF-ChIP data sets from Drosophila embryonic development. We built a cross-validation framework that compares a baseline model, based on the ChIP'ed (“primary”) TF's motif, to more complex models where binding by secondary TFs is hypothesized to influence the primary TF's occupancy. Candidates interacting TFs were chosen based on RNA-SEQ expression data from the time point of the ChIP experiment. We found widespread evidence of both cooperative and antagonistic effects by secondary TFs, and explicitly quantified these effects. We were able to identify multiple classes of interactions, including (1) long-range interactions between primary and secondary motifs (separated by ≤150 bp), suggestive of indirect effects such as chromatin remodeling, (2) short-range interactions with specific inter-site spacing biases, suggestive of direct physical interactions, and (3) overlapping binding sites suggesting competitive binding. Furthermore, by factoring out the previously reported strong correlation between TF occupancy and DNA accessibility, we were able to categorize the effects into those that are likely to be mediated by the secondary TF's effect on local accessibility and those that utilize accessibility-independent mechanisms. Finally, we conducted in vitro pull-down assays to test model-based predictions of short-range cooperative interactions

A role for histone deacetylases in the cellular and behavioral mechanisms underlying learning and memory.

PubMed

Mahgoub, Melissa; Monteggia, Lisa M

2014-10-01

Histone deacetylases (HDACs) are a family of chromatin remodeling enzymes that restrict access of transcription factors to the DNA, thereby repressing gene expression. In contrast, histone acetyltransferases (HATs) relax the chromatin structure allowing for an active chromatin state and promoting gene transcription. Accumulating data have demonstrated a crucial function for histone acetylation and histone deacetylation in regulating the cellular and behavioral mechanisms underlying synaptic plasticity and learning and memory. In trying to delineate the roles of individual HDACs, genetic tools have been used to manipulate HDAC expression in rodents, uncovering distinct contributions of individual HDACs in regulating the processes of memory formation. Moreover, recent findings have suggested an important role for HDAC inhibitors in enhancing learning and memory processes as well as ameliorating symptoms related to neurodegenerative diseases. In this review, we focus on the role of HDACs in learning and memory, as well as significant data emerging from the field in support of HDAC inhibitors as potential therapeutic targets for the treatment of cognitive disorders. © 2014 Mahgoub and Monteggia; Published by Cold Spring Harbor Laboratory Press.

HAMLET interacts with histones and chromatin in tumor cell nuclei.

PubMed

Düringer, Caroline; Hamiche, Ali; Gustafsson, Lotta; Kimura, Hiroshi; Svanborg, Catharina

2003-10-24

HAMLET is a folding variant of human alpha-lactalbumin in an active complex with oleic acid. HAMLET selectively enters tumor cells, accumulates in their nuclei and induces apoptosis-like cell death. This study examined the interactions of HAMLET with nuclear constituents and identified histones as targets. HAMLET was found to bind histone H3 strongly and to lesser extent histones H4 and H2B. The specificity of these interactions was confirmed using BIAcore technology and chromatin assembly assays. In vivo in tumor cells, HAMLET co-localized with histones and perturbed the chromatin structure; HAMLET was found associated with chromatin in an insoluble nuclear fraction resistant to salt extraction. In vitro, HAMLET bound strongly to histones and impaired their deposition on DNA. We conclude that HAMLET interacts with histones and chromatin in tumor cell nuclei and propose that this interaction locks the cells into the death pathway by irreversibly disrupting chromatin organization.

Occupational and genetic risk factors associated with intervertebral disc disease.

PubMed

Virtanen, Iita M; Karppinen, Jaro; Taimela, Simo; Ott, Jürg; Barral, Sandra; Kaikkonen, Kaisu; Heikkilä, Olli; Mutanen, Pertti; Noponen, Noora; Männikkö, Minna; Tervonen, Osmo; Natri, Antero; Ala-Kokko, Leena

2007-05-01

Cross-sectional epidemiologic study. To evaluate the interaction between known genetic risk factors and whole-body vibration for symptomatic intervertebral disc disease (IDD) in an occupational sample. Risk factors of IDD include, among others, whole-body vibration and heredity. In this study, the importance of a set of known genetic risk factors and whole-body vibration was evaluated in an occupational sample of train engineers and sedentary controls. Eleven variations in 8 genes (COL9A2, COL9A3, COL11A2, IL1A, IL1B, IL6, MMP-3, and VDR) were genotyped in 150 male train engineers with an average of 21-year exposure to whole-body vibration and 61 male paper mill workers with no exposure to vibration. Subjects were classified into IDD-phenotype and asymptomatic groups, based on the latent class analysis. The number of individuals belonging to the IDD-phenotype was significantly higher among train engineers (42% of train engineers vs. 17.5% of sedentary workers; P = 0.005). IL1A -889T allele represented a significant risk factor for the IDD-phenotype both in the single marker allelic association test (P = 0.043) and in the logistic regression analysis (P = 0.01). None of the other allele markers was significantly associated with symptoms when analyzed independently. However, for all the SNP markers considered, whole-body vibration represents a nominally significant risk factor. The results suggest that whole-body vibration is a risk factor for symptomatic IDD. Moreover, whole-body vibration had an additive effect with genetic risk factors increasing the likelihood of belonging to the IDD-phenotype group. Of the independent genetic markers, IL1A -889T allele had strongest association with IDD-phenotype.

Histone proteolysis: A proposal for categorization into ‘clipping’ and ‘degradation’

PubMed Central

Dhaenens, Maarten; Glibert, Pieter; Meert, Paulien; Vossaert, Liesbeth; Deforce, Dieter

2015-01-01

We propose for the first time to divide histone proteolysis into “histone degradation” and the epigenetically connoted “histone clipping”. Our initial observation is that these two different classes are very hard to distinguish both experimentally and biologically, because they can both be mediated by the same enzymes. Since the first report decades ago, proteolysis has been found in a broad spectrum of eukaryotic organisms. However, the authors often not clearly distinguish or determine whether degradation or clipping was studied. Given the importance of histone modifications in epigenetic regulation we further elaborate on the different ways in which histone proteolysis could play a role in epigenetics. Finally, unanticipated histone proteolysis has probably left a mark on many studies of histones in the past. In conclusion, we emphasize the significance of reviving the study of histone proteolysis both from a biological and an experimental perspective. PMID:25350939

Occupant Protection Project

NASA Technical Reports Server (NTRS)

Bopp, Genie; Somers, Jeff; Granderson, Brad; Gernhardt, Mike; Currie, Nancy; Lawrence, Chuck

2010-01-01

Topics include occupant protection overview with a focus on crew protection during dynamic phases of flight; occupant protection collaboration; modeling occupant protection; occupant protection considerations; project approach encompassing analysis tools, injury criteria, and testing program development; injury criteria update methodology, unique effects of pressure suits and other factors; and a summary.

Evaluation of Proteomic Search Engines for the Analysis of Histone Modifications

PubMed Central

2015-01-01

Identification of histone post-translational modifications (PTMs) is challenging for proteomics search engines. Including many histone PTMs in one search increases the number of candidate peptides dramatically, leading to low search speed and fewer identified spectra. To evaluate database search engines on identifying histone PTMs, we present a method in which one kind of modification is searched each time, for example, unmodified, individually modified, and multimodified, each search result is filtered with false discovery rate less than 1%, and the identifications of multiple search engines are combined to obtain confident results. We apply this method for eight search engines on histone data sets. We find that two search engines, pFind and Mascot, identify most of the confident results at a reasonable speed, so we recommend using them to identify histone modifications. During the evaluation, we also find some important aspects for the analysis of histone modifications. Our evaluation of different search engines on identifying histone modifications will hopefully help those who are hoping to enter the histone proteomics field. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the data set identifier PXD001118. PMID:25167464

Evaluation of proteomic search engines for the analysis of histone modifications.

PubMed

Yuan, Zuo-Fei; Lin, Shu; Molden, Rosalynn C; Garcia, Benjamin A

2014-10-03

Identification of histone post-translational modifications (PTMs) is challenging for proteomics search engines. Including many histone PTMs in one search increases the number of candidate peptides dramatically, leading to low search speed and fewer identified spectra. To evaluate database search engines on identifying histone PTMs, we present a method in which one kind of modification is searched each time, for example, unmodified, individually modified, and multimodified, each search result is filtered with false discovery rate less than 1%, and the identifications of multiple search engines are combined to obtain confident results. We apply this method for eight search engines on histone data sets. We find that two search engines, pFind and Mascot, identify most of the confident results at a reasonable speed, so we recommend using them to identify histone modifications. During the evaluation, we also find some important aspects for the analysis of histone modifications. Our evaluation of different search engines on identifying histone modifications will hopefully help those who are hoping to enter the histone proteomics field. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the data set identifier PXD001118.

Histone H3 phosphorylation near the nucleosome dyad alters chromatin structure

PubMed Central

North, Justin A.; Šimon, Marek; Ferdinand, Michelle B.; Shoffner, Matthew A.; Picking, Jonathan W.; Howard, Cecil J.; Mooney, Alex M.; van Noort, John; Poirier, Michael G.; Ottesen, Jennifer J.

2014-01-01

Nucleosomes contain ∼146 bp of DNA wrapped around a histone protein octamer that controls DNA accessibility to transcription and repair complexes. Posttranslational modification (PTM) of histone proteins regulates nucleosome function. To date, only modest changes in nucleosome structure have been directly attributed to histone PTMs. Histone residue H3(T118) is located near the nucleosome dyad and can be phosphorylated. This PTM destabilizes nucleosomes and is implicated in the regulation of transcription and repair. Here, we report gel electrophoretic mobility, sucrose gradient sedimentation, thermal disassembly, micrococcal nuclease digestion and atomic force microscopy measurements of two DNA–histone complexes that are structurally distinct from nucleosomes. We find that H3(T118ph) facilitates the formation of a nucleosome duplex with two DNA molecules wrapped around two histone octamers, and an altosome complex that contains one DNA molecule wrapped around two histone octamers. The nucleosome duplex complex forms within short ∼150 bp DNA molecules, whereas altosomes require at least ∼250 bp of DNA and form repeatedly along 3000 bp DNA molecules. These results are the first report of a histone PTM significantly altering the nucleosome structure. PMID:24561803

Evaluation of occupational allergic contact dermatitis and its related factors in Iran.

PubMed

Nassiri-Kashani, Mansour; Nassiri-Kashani, Mohammad Hassan; Ghafari, Mostafa

2016-01-01

Background: Occupational contact dermatitis, especially in hand, is one of the most common occupational disorders. The present study aimed at evaluating patients with occupational allergic contact dermatitis (ACD) caused by common allergens based on occupation type and disease history. Methods: This cross-sectional study aimed at evaluating the data of the patients with probable diagnosis of ACD in Center for Research and Training in Skin Diseases and Leprosy (CRTSDL) in Iran. In the present study, 946 patients were assessed from different regions of Iran. One hundred fifty-one cases with positive patch test and relevant exposure were entered into the study; data related to their occupation and disease activity history were evaluated and recorded. Then, factors related to disease activity history were assessed considering the occupational groups and common exposures. Results: Nickel sulphate was the most common allergen in the 151 patients. Disease activity was constant in 29.8% of the patients; it increased in 27.8%, and decreased just before doing the patch test in 42.4%. Of the patients, 52.3% were getting worse during the working days. Occupational groups were significantly different in age and gender. Disease duration was also different in the occupational groups (p=0.001). The least disease duration was observed in healthcare workers, and the most in service workers. Lesions in the foot were related to period of employment. In administrative work group, (teachers, technicians and housewives) disease activity was decreased in the most cases, while it was increased in most patients of service workers (p=0.086). Conclusion: The present study, similar to previous reports, revealed that nickel sulphate is the most common allergen in ACD cases. Moreover, it was found that the symptoms of disease activity remained constant or increased in a significant proportion of the cases during the working days. Therefore, these workers should seriously follow up on this matter

[Concomitant influence of occupational and social risk factors on health of workers engaged into powder metallurgy].

PubMed

Shur, P Z; Zaĭtseva, N V; Kostarev, V G; Lebedeva-Nesevria, N A; Shliapnikov, D M

2012-01-01

Results of health risk evaluation in workers engaged into powder metallurgy, using complex of hygienic, medical, epidemiologic and sociologic studies, enable to define priority occupational and social risk factors, to assess degree of their influence on the workers' health and to identify occupationally induced diseases.

Genomic maps of lincRNA occupancy reveal principles of RNA-chromatin interactions

PubMed Central

Chu, Ci; Qu, Kun; Zhong, Franklin; Artandi, Steven E.; Chang, Howard Y.

2011-01-01

SUMMARY Long intergenic noncoding RNAs (lincRNAs) are key regulators of chromatin state, yet the nature and sites of RNA-chromatin interaction are mostly unknown. Here we introduce Chromatin Isolation by RNA Purification (ChIRP), where tiling oligonucleotides retrieve specific lincRNAs with bound protein and DNA sequences, which are enumerated by deep sequencing. ChIRP-seq of three lincRNAs reveal that RNA occupancy sites in the genome are focal, sequence-specific, and numerous. Drosophila roX2 RNA occupies male X-linked gene bodies with increasing tendency toward the 3’ end, peaking at CES sites. Human telomerase RNA TERC occupies telomeres and Wnt pathway genes. HOTAIR lincRNA preferentially occupies a GA-rich DNA motif to nucleate broad domains of Polycomb occupancy and histone H3 lysine 27 trimethylation. HOTAIR occupancy occurs independently of EZH2, suggesting the order of RNA guidance of Polycomb occupancy. ChIRP-seq is generally applicable to illuminate the intersection of RNA and chromatin with newfound precision genome-wide. PMID:21963238

Histone-poly(A) hybrid molecules as tools to block nuclear pores.

PubMed

Cremer, G; Wojtech, E; Kalbas, M; Agutter, P S; Prochnow, D

1995-04-01

Histone-poly(A) hybrid molecules were used for transport experiments with resealed nuclear envelopes and after attachment of a cleavable cross-linker (SASD) to identify nuclear proteins. In contrast to histones, the hybrid molecules cannot be accumulated in resealed nuclear envelopes, and in contrast to poly(A), the export of hybrids from preloaded nuclear envelopes is completely impaired. The experiments strongly confirm the existence of poly(A) as an export signal in mRNA which counteracts the nuclear location signals (NLS) in histones. The contradicting transport signals in the hybrid molecules impair translocation through the nuclear pore complex. The failure to accumulate hybrid molecules into resealed nuclear envelopes results from the covalent attachment of polyadenylic acid to histones in a strict 1:1 molar ratio. This was demonstrated in control transport experiments where radiolabeled histones were simply mixed with nonlabeled poly(A) or radiolabeled poly(A) mixed with nonlabeled histones. In comparison, control uptake experiments with histones covalently linked to a single UMP-mononucleotide are strongly enhanced. Such controls exclude the conceivable possibility of a simple masking of the nuclear location signal in the histones by the covalent attached poly(A) moiety. Photoreactive histone-poly(A) hybrid analogs serve to identify nuclear envelope proteins--presumably in the nuclear pore--with molecular weights of 110, 80, and 71.4 kDa.

Extracellular DNA and histones: double-edged swords in immunothrombosis.

PubMed

Gould, T J; Lysov, Z; Liaw, P C

2015-06-01

The existence of extracellular DNA in human plasma, also known as cell-free DNA (cfDNA), was first described in the 1940s. In recent years, there has been a resurgence of interest in the functional significance of cfDNA, particularly in the context of neutrophil extracellular traps (NETs). cfDNA and histones are key components of NETs that aid in the host response to infection and inflammation. However, cfDNA and histones may also exert harmful effects by triggering coagulation, inflammation, and cell death and by impairing fibrinolysis. In this article, we will review the pathologic nature of cfDNA and histones in macrovascular and microvascular thrombosis, including venous thromboembolism, cancer, sepsis, and trauma. We will also discuss the prognostic value of cfDNA and histones in these disease states. Understanding the molecular and cellular pathways regulated by cfDNA and histones may provide novel insights to prevent pathological thrombus formation and vascular occlusion. © 2015 International Society on Thrombosis and Haemostasis.

Histone modifications controlling native and induced neural stem cell identity.

PubMed

Broccoli, Vania; Colasante, Gaia; Sessa, Alessandro; Rubio, Alicia

2015-10-01

During development, neural progenitor cells (NPCs) that are capable of self-renewing maintain a proliferative cellular pool while generating all differentiated neural cell components. Although the genetic network of transcription factors (TFs) required for neural specification has been well characterized, the unique set of histone modifications that accompanies this process has only recently started to be investigated. In vitro neural differentiation of pluripotent stem cells is emerging as a powerful system to examine epigenetic programs. Deciphering the histone code and how it shapes the chromatin environment will reveal the intimate link between epigenetic changes and mechanisms for neural fate determination in the developing nervous system. Furthermore, it will offer a molecular framework for a stringent comparison between native and induced neural stem cells (iNSCs) generated by direct neural cell conversion. Copyright © 2015 Elsevier Ltd. All rights reserved.

Esperanto for histones: CENP-A, not CenH3, is the centromeric histone H3 variant.

PubMed

Earnshaw, W C; Allshire, R C; Black, B E; Bloom, K; Brinkley, B R; Brown, W; Cheeseman, I M; Choo, K H A; Copenhaver, G P; Deluca, J G; Desai, A; Diekmann, S; Erhardt, S; Fitzgerald-Hayes, M; Foltz, D; Fukagawa, T; Gassmann, R; Gerlich, D W; Glover, D M; Gorbsky, G J; Harrison, S C; Heun, P; Hirota, T; Jansen, L E T; Karpen, G; Kops, G J P L; Lampson, M A; Lens, S M; Losada, A; Luger, K; Maiato, H; Maddox, P S; Margolis, R L; Masumoto, H; McAinsh, A D; Mellone, B G; Meraldi, P; Musacchio, A; Oegema, K; O'Neill, R J; Salmon, E D; Scott, K C; Straight, A F; Stukenberg, P T; Sullivan, B A; Sullivan, K F; Sunkel, C E; Swedlow, J R; Walczak, C E; Warburton, P E; Westermann, S; Willard, H F; Wordeman, L; Yanagida, M; Yen, T J; Yoda, K; Cleveland, D W

2013-04-01

The first centromeric protein identified in any species was CENP-A, a divergent member of the histone H3 family that was recognised by autoantibodies from patients with scleroderma-spectrum disease. It has recently been suggested to rename this protein CenH3. Here, we argue that the original name should be maintained both because it is the basis of a long established nomenclature for centromere proteins and because it avoids confusion due to the presence of canonical histone H3 at centromeres.

Factors influencing the perceived quality of clinical supervision of occupational therapists in a large Australian state.

PubMed

Martin, Priya; Kumar, Saravana; Lizarondo, Lucylynn; Tyack, Zephanie

2016-10-01

Clinical supervision is important for effective health service delivery, professional development and practice. Despite its importance there is a lack of evidence regarding the factors that improve its quality. This study aimed to investigate the factors that influence the quality of clinical supervision of occupational therapists employed in a large public sector health service covering mental health, paediatrics, adult physical and other practice areas. A mixed method, sequential explanatory study design was used consisting of two phases. This article reports the quantitative phase (Phase One) which involved administration of the Manchester Clinical Supervision Scale (MCSS-26) to 207 occupational therapists. Frequency of supervision sessions, choice of supervisor and the type of supervision were found to be the predictor variables with a positive and significant influence on the quality of clinical supervision. Factors such as age, length of supervision and the area of practice were found to be the predictor variables with a negative and significant influence on the quality of clinical supervision. Factors that influence the perceived quality of clinical supervision among occupational therapists have been identified. High quality clinical supervision is an important component of clinical governance and has been shown to be beneficial to practitioners, patients and the organisation. Information on factors that make clinical supervision effective identified in this study can be added to existing supervision training and practices to improve the quality of clinical supervision. © 2016 Occupational Therapy Australia.

Inequities in exposure to occupational risk factors between Māori and non-Māori workers in Aotearoa New Zealand.

PubMed

Denison, Hayley J; Eng, Amanda; Barnes, Lucy A; Cheng, Soo; 't Mannetje, Andrea; Haddock, Katharine; Douwes, Jeroen; Pearce, Neil; Ellison-Loschmann, Lis

2018-05-02

Health inequities between indigenous and non-indigenous people are well documented. However, the contribution of differential exposure to risk factors in the occupational environment remains unclear. This study assessed differences in the prevalence of self-reported exposure to disease risk factors, including dust and chemicals, physical factors and organisational factors, between Māori and non-Māori workers in New Zealand. Potential participants were sampled from the New Zealand electoral rolls and invited to take part in a telephone interview, which included questions about current workplace exposures. Logistic regression, accounting for differences in age, socioeconomic status and occupational distribution between Māori and non-Māori, was used to assess differences in exposures. In total, 2344 Māori and 2710 non-Māori participants were included in the analyses. Māori had greater exposure to occupational risk factors than non-Māori. For dust and chemical exposures, the main differences related to Māori working in occupations where these exposures are more common. However, even within the same job, Māori were more likely to be exposed to physical factors such as heavy lifting and loud noise, and organisational factors such as carrying out repetitive tasks and working to tight deadlines compared with non-Māori. This is one of the first studies internationally to compare occupational risk factors between indigenous and non-indigenous people. These findings suggest that the contribution of the occupational environment to health inequities between Māori and non-Māori has been underestimated and that work tasks may be unequally distributed according to ethnicity. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin

PubMed Central

Bochyńska, Agnieszka; Lüscher-Firzlaff, Juliane

2018-01-01

Regulation of gene expression is achieved by sequence-specific transcriptional regulators, which convey the information that is contained in the sequence of DNA into RNA polymerase activity. This is achieved by the recruitment of transcriptional co-factors. One of the consequences of co-factor recruitment is the control of specific properties of nucleosomes, the basic units of chromatin, and their protein components, the core histones. The main principles are to regulate the position and the characteristics of nucleosomes. The latter includes modulating the composition of core histones and their variants that are integrated into nucleosomes, and the post-translational modification of these histones referred to as histone marks. One of these marks is the methylation of lysine 4 of the core histone H3 (H3K4). While mono-methylation of H3K4 (H3K4me1) is located preferentially at active enhancers, tri-methylation (H3K4me3) is a mark found at open and potentially active promoters. Thus, H3K4 methylation is typically associated with gene transcription. The class 2 lysine methyltransferases (KMTs) are the main enzymes that methylate H3K4. KMT2 enzymes function in complexes that contain a necessary core complex composed of WDR5, RBBP5, ASH2L, and DPY30, the so-called WRAD complex. Here we discuss recent findings that try to elucidate the important question of how KMT2 complexes are recruited to specific sites on chromatin. This is embedded into short overviews of the biological functions of KMT2 complexes and the consequences of H3K4 methylation. PMID:29498679

Modeling of Individual and Organizational Factors Affecting Traumatic Occupational Injuries Based on the Structural Equation Modeling: A Case Study in Large Construction Industries

PubMed Central

Mohammadfam, Iraj; Soltanzadeh, Ahmad; Moghimbeigi, Abbas; Akbarzadeh, Mehdi

2016-01-01

Background Individual and organizational factors are the factors influencing traumatic occupational injuries. Objectives The aim of the present study was the short path analysis of the severity of occupational injuries based on individual and organizational factors. Materials and Methods The present cross-sectional analytical study was implemented on traumatic occupational injuries within a ten-year timeframe in 13 large Iranian construction industries. Modeling and data analysis were done using the structural equation modeling (SEM) approach and the IBM SPSS AMOS statistical software version 22.0, respectively. Results The mean age and working experience of the injured workers were 28.03 ± 5.33 and 4.53 ± 3.82 years, respectively. The portions of construction and installation activities of traumatic occupational injuries were 64.4% and 18.1%, respectively. The SEM findings showed that the individual, organizational and accident type factors significantly were considered as effective factors on occupational injuries’ severity (P < 0.05). Conclusions Path analysis of occupational injuries based on the SEM reveals that individual and organizational factors and their indicator variables are very influential on the severity of traumatic occupational injuries. So, these should be considered to reduce occupational accidents’ severity in large construction industries. PMID:27800465

Occupational Therapy for Patients With Acute Lung Injury: Factors Associated With Time to First Intervention in the Intensive Care Unit

PubMed Central

Dinglas, Victor D.; Colantuoni, Elizabeth; Ciesla, Nancy; Mendez-Tellez, Pedro A.; Shanholtz, Carl

2013-01-01

OBJECTIVE. Very early occupational therapy intervention in the intensive care unit (ICU) improves patients’ physical recovery. We evaluated the association of patient, ICU, and hospital factors with time to first occupational therapy intervention in ICU patients with acute lung injury (ALI). METHOD. We conducted a prospective cohort study of 514 consecutive patients with ALI from 11 ICUs in three hospitals in Baltimore, MD. RESULTS. Only 30% of patients ever received occupational therapy during their ICU stay. Worse organ failure, continuous hemodialysis, and uninterrupted continuous infusion of sedation were independently associated with delayed occupational therapy initiation, and hospital study site and admission to a trauma ICU were independently associated with earlier occupational therapy. CONCLUSION. Severity of illness and ICU practices for sedation administration were associated with delayed occupational therapy. Both hospital study site and type of ICU were independently associated with timing of occupational therapy, indicating modifiable environmental factors for promoting early occupational therapy in the ICU. PMID:23597694

HDT701, a histone H4 deacetylase, negatively regulates plant innate immunity by modulating histone H4 acetylation of defense-related genes in rice.

PubMed

Ding, Bo; Bellizzi, Maria del Rosario; Ning, Yuese; Meyers, Blake C; Wang, Guo-Liang

2012-09-01

Histone acetylation and deacetylation play an important role in the modification of chromatin structure and regulation of gene expression in eukaryotes. Chromatin acetylation status is modulated antagonistically by histone acetyltransferases and histone deacetylases (HDACs). In this study, we characterized the function of histone deacetylase701 (HDT701), a member of the plant-specific HD2 subfamily of HDACs, in rice (Oryza sativa) innate immunity. Transcription of HDT701 is increased in the compatible reaction and decreased in the incompatible reaction after infection by the fungal pathogen Magnaporthe oryzae. Overexpression of HDT701 in transgenic rice leads to decreased levels of histone H4 acetylation and enhanced susceptibility to the rice pathogens M. oryzae and Xanthomonas oryzae pv oryzae (Xoo). By contrast, silencing of HDT701 in transgenic rice causes elevated levels of histone H4 acetylation and elevated transcription of pattern recognition receptor (PRR) and defense-related genes, increased generation of reactive oxygen species after pathogen-associated molecular pattern elicitor treatment, as well as enhanced resistance to both M. oryzae and Xoo. We also found that HDT701 can bind to defense-related genes to regulate their expression. Taken together, these results demonstrate that HDT701 negatively regulates innate immunity by modulating the levels of histone H4 acetylation of PRR and defense-related genes in rice.

Occupational and environmental risk factors for chronic rhinosinusitis: a systematic review.

PubMed

Sundaresan, Agnes S; Hirsch, Annemarie G; Storm, Margaret; Tan, Bruce K; Kennedy, Thomas L; Greene, J Scott; Kern, Robert C; Schwartz, Brian S

2015-11-01

Chronic rhinosinusitis (CRS) is a prevalent and disabling paranasal sinus disease, with a likely multifactorial etiology potentially including hazardous occupational and environmental exposures. We completed a systematic review of the occupational and environmental literature to evaluate the quality of evidence of the role that hazardous exposures might play in CRS. We searched PubMed for studies of CRS and following exposure categories: occupation, employment, work, industry, air pollution, agriculture, farming, environment, chemicals, roadways, disaster, and traffic. We abstracted information from the final set of articles across 6 primary domains: study design; population; exposures evaluated; exposure assessment; CRS definition; and results. We identified 41 articles from 1080 manuscripts: 37 occupational risk papers, 1 environmental risk paper, and 3 papers studying both categories of exposures. None of the 41 studies used a CRS definition consistent with current diagnostic guidelines. Exposure assessment was generally dependent on self-report or binary measurements of exposure based on industry of employment. Only grain, dairy, and swine operations among farmers were evaluated by more than 1 study using a common approach to defining CRS, but employment in these settings was not consistently associated with CRS. The multiple other exposures did not meet quality standards for reporting associations or were not evaluated by more than 1 study. The current state of the literature allows us to make very few conclusions about the role of hazardous occupational or environmental exposures in CRS, leaving a critical knowledge gap regarding potentially modifiable risk factors for disease onset and progression. © 2015 ARS-AAOA, LLC.

Isolation and characterization of an osmotic stress and ABA induced histone deacetylase in Arachis hygogaea

PubMed Central

Su, Liang-Chen; Deng, Bin; Liu, Shuai; Li, Li-Mei; Hu, Bo; Zhong, Yu-Ting; Li, Ling

2015-01-01

Histone acetylation, which together with histone methylation regulates gene activity in response to stress, is an important epigenetic modification. There is an increasing research focus on histone acetylation in crops, but there is no information to date in peanut (Arachis hypogaea). We showed that osmotic stress and ABA affect the acetylation of histone H3 loci in peanut seedlings by immunoblotting experiments. Using RNA-seq data for peanut, we found a RPD3/HDA1-like superfamily histone deacetylase (HDAC), termed AhHDA1, whose gene is up-regulated by PEG-induced water limitation and ABA signaling. We isolated and characterized AhHDA1 from A. hypogaea, showing that AhHDA1 is very similar to an Arabidopsis HDAC (AtHDA6) and, in recombinant form, possesses HDAC activity. To understand whether and how osmotic stress and ABA mediate the peanut stress response by epigenetics, the expression of AhHDA1 and stress-responsive genes following treatment with PEG, ABA, and the specific HDAC inhibitor trichostatin A (TSA) were analyzed. AhHDA1 transcript levels were enhanced by all three treatments, as was expression of peanut transcription factor genes, indicating that AhHDA1 might be involved in the epigenetic regulation of stress resistance genes that comprise the responses to osmotic stress and ABA. PMID:26217363

[An investigation of psychological state at different stages of occupational AIDS exposure and related influencing factors in Nanning, China].

PubMed

Lin, Q; Ge, X M; Mo, J C; Li, S S; Chen, C C; Chen, S Y

2016-10-20

Objective: To investigate the changes in psychological state after occupational exposure in the AIDS occupational exposure population and related influencing factors, and to provide baseline data and a basis for related departments to conduct mental health prevention and intervention for personnel with occupational AIDS exposure. Methods: AIDS risk assessment was performed for all personnel with occupational AIDS exposure in 2014 in Nanning, China, and the Symptom Checklist - 90 (SCL - 90) psychological scale was used for psychological state evaluation at 24 hours, 1 week, and 3 months after occupational exposure in all persons who met the research criteria. Results: Most of the persons with occupational AIDS exposure came from secondary and tertiary hospitals (85%) , and nurses accounted for the highest percentage (78.3% ). The age ranged from 21 to 50 years, and the mean age was 31.02 ± 7.92 years. The persons with occupational AIDS exposure aged 20~29 years accounted for the highest percentage (51.6%) , and most persons (76.7%) graduated from junior colleges. Compared with the adult norm, there was significant increases in the total psychological score and the number of positive items after occupational exposure ( P <0.05). The scores of all items at 24 hours were significantly higher than those at the other time points, and the scores of all items gradually decreased over time ( F =227.24, 267.57, and 287.46, P <0.05). Compared with the adult norm, there were significant increases in the factor points at 24 hours and significant reductions in the factor points at 3 months ( P <0.05). Compared with those at 24 hours, the factor scores at 3 months decreased significantly ( P <0.05). Conclusion: Occupational AIDS exposure affects the mental status of related personnel, and the mental status at 24 hours after exposure is poor. Related departments should provide corresponding psychological counseling for the occupational exposure population at different exposure

Disruption of Higher-Order Folding by Core Histone Acetylation Dramatically Enhances Transcription of Nucleosomal Arrays by RNA Polymerase III

PubMed Central

Tse, Christin; Sera, Takashi; Wolffe, Alan P.; Hansen, Jeffrey C.

1998-01-01

We have examined the effects of core histone acetylation on the transcriptional activity and higher-order folding of defined 12-mer nucleosomal arrays. Purified HeLa core histone octamers containing an average of 2, 6, or 12 acetates per octamer (8, 23, or 46% maximal site occupancy, respectively) were assembled onto a DNA template consisting of 12 tandem repeats of a 208-bp Lytechinus 5S rRNA gene fragment. Reconstituted nucleosomal arrays were transcribed in a Xenopus oocyte nuclear extract and analyzed by analytical hydrodynamic and electrophoretic approaches to determine the extent of array compaction. Results indicated that in buffer containing 5 mM free Mg2+ and 50 mM KCl, high levels of acetylation (12 acetates/octamer) completely inhibited higher-order folding and concurrently led to a 15-fold enhancement of transcription by RNA polymerase III. The molecular mechanisms underlying the acetylation effects on chromatin condensation were investigated by analyzing the ability of differentially acetylated nucleosomal arrays to fold and oligomerize. In MgCl2-containing buffer the folding of 12-mer nucleosomal arrays containing an average of two or six acetates per histone octamer was indistinguishable, while a level of 12 acetates per octamer completely disrupted the ability of nucleosomal arrays to form higher-order folded structures at all ionic conditions tested. In contrast, there was a linear relationship between the extent of histone octamer acetylation and the extent of disruption of Mg2+-dependent oligomerization. These results have yielded new insight into the molecular basis of acetylation effects on both transcription and higher-order compaction of nucleosomal arrays. PMID:9671473

[Occupational risk factors and perceptions of air pollution by motorcycle taxi drivers in Cotonou, Benin].

PubMed

Lawin, Hervé; Ayi Fanou, Lucie; Hinson, Vikkey; Tollo, Brice; Fayomi, Benjamin; Ouendo, Edgard-Marius

Motorcycle taxis occupy a major place in urban transport. Motorcycle taxi drivers are exposed to occupational risk factors (ORF) including air pollution. The objective of this study was to evaluate these ORF among motorcycle taxi drivers and their perceptions of air pollution. This mixed study was conducted on motorcycle taxi drivers in Cotonou. The qualitative study was based on focus groups concerning 16 items from the Participatory Occupational Risk Screening Guide (DEPARIS) until saturation and after triangulation of data. The quantitative study consisted of administering a questionnaire addressing socioeconomic and demographic characteristics, cardiopulmonary diseases, and perception of air -pollution risk factors among 397 Cotonou motorcycle taxi drivers. Drivers perceived poor road conditions, effort and handling, and lack of social security as unsatisfactory ORF. Their mean age was 40.95 ± 8.75 years and 45.84% had primary -education. They had been working as motorcycle taxi drivers for an average of 134.95 ± 101.53 months with an average income of FCFA 3138 ± 1238. These occupational factors were significantly associated with cardiopulmonary disorders, observed in 63.2% of drivers. Less than 1/3 of drivers felt that air pollution affected their personal health. Motorcycle taxi drivers have a poor perception of ORF and the severity of exposure to air pollution in this occupation. There is a need to take action to promote the health of this population.

Prenatal dexamethasone exposure in rats results in long-term epigenetic histone modifications and tumour necrosis factor-α production decrease.

PubMed

Yu, Hong-Ren; Kuo, Ho-Chang; Chen, Chih-Cheng; Sheen, Jiunn-Ming; Tiao, Mao-Meng; Chen, Yu-Chieh; Chang, Kow-Aung; Tain, You-Lin; Huang, Li-Tung

2014-12-01

Glucocorticoid (GC) is often given when preterm delivery is expected. This treatment is successful in stimulating the development of the fetal lung. However, reports and related research regarding the prolonged effects of prenatal GC on the development of immunity are very limited. Some data, derived from infants whose mothers were given immunosuppressants during pregnancy for the treatment of autoimmune disorders, suggest that prenatal exposure to GC may have only a limited effect on the development of the immune system. What is unknown is whether the immune modulation effects of prenatal GC might appear at a later childhood stage and beyond. Here we evaluated the immune programming influenced by prenatal GC. Pregnant Sprague-Dawley rats received dexamethasone (DEX; 0.1 mg/kg/day) or saline at gestational days 14-20. Male offspring were killed at day 7 or day 120 after birth. Spleens were collected for immune study. Of the inflammation mediators, matrix metalloproteinase-9, tumour necrosis factor-α (TNF-α) and granulocyte-macrophage colony-stimulating factor mRNAs decreased in the prenatal DEX group at an early stage after birth. Upon concanavalin A stimulation, prenatal DEX treatment reduced TNF-α production, but not interferon-γ production, by splenocytes at day 120 after birth compared with the vehicle group. Decreased levels of active chromatin signs (acetylation of histone H3 lysines, H3K4me1/3, and H3K36me3) in TNF-α promoter were compatible with the expressions of TNF-α. Our results suggest that prenatal DEX has a profound and lasting impact on the developing immune system even to the adult stage. Epigenetic histone modifications regulate TNF-α expression following prenatal DEX in rats. © 2014 John Wiley & Sons Ltd.

[Evaluation of occupational risk factors, nutritional habits and nutritional status in industrial workers].

PubMed

Domagała-Dobrzycka, M

2000-01-01

The objective of this study was to examine the relationship between selected risk factors at the workplace and health indices in relation to nutritional habits and nutritional status in industrial workers. Exposure to physical and chemical risk factors and their impact on health in the province of Szczecin and in Poland was evaluated basing on data published in the Yearbooks of the Province of Szczecin, the Central Statistics Bureau (GUS) and Regional Inspectorate of Labor (OIP) in Szczecin. A random selection of plants in Szczecin was done and workplaces with chemical and physical risk levels exceeding the highest acceptable values were identified. Measurements of concentrations of chemicals and intensity of physical factors were performed by Work Environment Research Laboratories of the plants and by the laboratory of the Sanitary and Epidemiological Center in Szczecin. Eighty-eight men exposed to occupational risk factors were randomly selected. The mean period of exposure in that group was approximately ten years. The control group was composed of male workers (n = 83) not exposed to any of the risk factors in question (Tab. 3). Nutritional habits and nutritional status were studied during summer/autumn and winter/spring periods. Dietary survey consisted of the last 24-hour nutrient intake questionnaire. Nutritional status evaluation was based on body mass index (BMI) values and results of the following laboratory tests: blood cell count, levels of total protein, prealbumin, retinol binding protein (RBP), magnesium, inorganic phosphorus, and ascorbic acid. The following results were obtained: 1. Physical factors constituted the most frequent source of occupational risk in the province of Szczecin and in Poland in 1990-1994 (Tab. 1); 2. The incidence of occupational risk and occupational disease morbidity rates in 1990-1994 were lower for the province of Szczecin than the average for Poland; 3. The rate of fatal accidents at work in 1982-1994 was higher for the

The Magnitude of Mortality from Ischemic Heart Disease Attributed to Occupational Factors in Korea - Attributable Fraction Estimation Using Meta-analysis.

PubMed

Ha, Jaehyeok; Kim, Soo-Geun; Paek, Domyung; Park, Jungsun

2011-03-01

Ischemic heart disease (IHD) is a major cause of death in Korea and known to result from several occupational factors. This study attempted to estimate the current magnitude of IHD mortality due to occupational factors in Korea. After selecting occupational risk factors by literature investigation, we calculated attributable fractions (AFs) from relative risks and exposure data for each factor. Relative risks were estimated using meta-analysis based on published research. Exposure data were collected from the 2006 Survey of Korean Working Conditions. Finally, we estimated 2006 occupation-related IHD mortality. FOR THE FACTORS CONSIDERED, WE ESTIMATED THE FOLLOWING RELATIVE RISKS: noise 1.06, environmental tobacco smoke 1.19 (men) and 1.22 (women), shift work 1.12, and low job control 1.15 (men) and 1.08 (women). Combined AFs of those factors in the IHD were estimated at 9.29% (0.3-18.51%) in men and 5.78% (-7.05-19.15%) in women. Based on these fractions, Korea's 2006 death toll from occupational IHD between the age of 15 and 69 was calculated at 353 in men (total 3,804) and 72 in women (total 1,246). We estimated occupational IHD mortality of Korea with updated data and more relevant evidence. Despite the efforts to obtain reliable estimates, there were many assumptions and limitations that must be overcome. Future research based on more precise design and reliable evidence is required for more accurate estimates.

Mechanism of histone survival during transcription by RNA polymerase II

PubMed Central

Kulaeva, Olga I

2010-01-01

Transcription of eukaryotic genes by RNA polymerase II is typically accompanied by minimal exchange of histones H3/H4 carrying various covalent modifications. In vitro studies suggest that histone survival is accompanied by the formation of a small transient DNA loop on the surface of the histone octamer including a molecule of transcribing enzyme. PMID:21326897

Low back pain characterized by muscle resistance and occupational factors associated with nursing1

PubMed Central

Petersen, Rafael de Souza; Marziale, Maria Helena Palucci

2014-01-01

Objective to identify the occupational factors associated with low back pain using a surveillance tool and to characterize the low back pain by the resistance of the extensor muscles of the vertebral column among nursing professionals at an Intensive Care Unit. Methods Cross-sectional study. The workers answered a questionnaire about occupational factors and participated in a resistance test of the extensor muscles of the vertebral column. Associations were established through Student's T-test or Mann-Whitney's U-test and correlations using Pearson's test. Results Out of 48 participants, 32 (67%) suffered from low pain. For the resistance test, the subjects suffering from low back pain endured less time in comparison with asymptomatic subjects, but without significant differences (p=0.147). The duration of the pain episode showed a significant negative correlation (p=0.016) with the results of the resistance test though. The main factors identified as causes of low back pain were biomechanical and postural elements, conditions of the muscle structure and physical and organizational conditions. Conclusions the main occupational factors associated with the low back pain were the posture and the characteristics of the physical and organizational conditions. In addition, the extensor muscles of the column showed a trend towards lesser resistance for workers in pain. This evidence is important when considering prevention and treatment strategies. PMID:25029048

The Role of Histone Protein Modifications and Mutations in Histone Modifiers in Pediatric B-Cell Progenitor Acute Lymphoblastic Leukemia

PubMed Central

Janczar, Szymon; Janczar, Karolina; Pastorczak, Agata; Harb, Hani; Paige, Adam J. W.; Zalewska-Szewczyk, Beata; Danilewicz, Marian; Mlynarski, Wojciech

2017-01-01

While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis. PMID:28054944

Voice disorders in teachers: occupational risk factors and psycho-emotional factors.

PubMed

van Houtte, Evelyne; Claeys, Sofie; Wuyts, Floris; van Lierde, Kristiane

2012-10-01

Teaching is a high-risk occupation for developing voice disorders. The purpose of this study was to investigate previously described vocal risk factors as well as to identify new risk factors related to both the personal life of the teacher (fluid intake, voice-demanding activities, family history of voice disorders, and children at home) and to environmental factors (temperature changes, chalk use, presence of curtains, carpet, or air-conditioning, acoustics in the classroom, and noise in and outside the classroom). The study group comprised 994 teachers (response rate 46.6%). All participants completed a questionnaire. Chi-square tests and logistic regression analyses were performed. A total of 51.2% (509/994) of the teachers presented with voice disorders. Women reported more voice disorders compared to men (56.4% versus 40.4%, P < 0.001). Vocal risk factors were a family history of voice disorders (P = 0.005), temperature changes in the classroom (P = 0.017), the number of pupils per classroom (P = 0.001), and noise level inside the classroom (P = 0.001). Teachers with voice disorders presented a higher level of psychological distress (P < 0.001) compared to teachers without voice problems. Voice disorders are frequent among teachers, especially in female teachers. The results of this study emphasize that multiple factors are involved in the development of voice disorders.

Awareness of Occupational Hazards and Associated Factors among Automobile Repair Artisans in Kathmandu Metropolitan City, Nepal

PubMed Central

Marahatta, Sujan B.; Gautam, Sanju; Paudel, Grish; Yadav, Uday N.

2018-01-01

Background: An occupational hazard contributes to severe health problems among workers due to unhygienic conditions and lack of safety at the workplace. Economic growth and productivity can be well achieved by promoting health, safety, and improved quality workplace. Aims: To assess the knowledge of occupational hazards, use of Personal Protective Equipment (PPE) and the factors associated with awareness on occupational hazards among automobile repair artisans in Kathmandu, Nepal. Settings and Design: A quantitative descriptive cross-sectional study with 400 automobile repair artisans from Kathmandu metropolitan city was conducted between March and September, 2015. Materials and Methods: Simple random sampling was adopted for recruiting study participants. Pre-tested, validated semi-structured questionnaire was used in line with study objectives to collect the data. Statistical Analysis: Logistic regression analysis was employed to identify factors associated with the awareness of occupational hazard and PPE use. Results: Of total, 56% had awareness on occupational hazard and 44.3% of artisans were using the personal protective equipments. Being educated, having job duration ≥6 years and having pre-service training for work were significantly associated with the awareness of occupational hazards. Notably, we found that those who were aware of occupational hazard (OR = 3.01, 95% CI: 1.98–4.57) were three times more likely to use the safety measures when compared to those who were unaware. Conclusions: Awareness on occupational hazard and use of PPE is very low among automobile repair artisans in Kathmandu, Nepal. Therefore, interventions on awareness raising on areas, like provision of pre-service training, promotion of safety advocacy, and enforcement of appropriate regulations for work place. PMID:29743786

Transcription factor Sox4 is required for PUMA-mediated apoptosis induced by histone deacetylase inhibitor, TSA.

PubMed

Jang, Sang-Min; Kang, Eun-Jin; Kim, Jung-Woong; Kim, Chul-Hong; An, Joo-Hee; Choi, Kyung-Hee

2013-08-23

PUMA is a crucial regulator of apoptotic cell death mediated by p53-dependent and p53-independent mechanisms. In many cancer cells, PUMA expression is induced in response to DNA-damaging reagent in a p53-dependent manner. However, few studies have investigated transcription factors that lead to the induction of PUMA expression via p53-independent apoptotic signaling. In this study, we found that the transcription factor Sox4 increased PUMA expression in response to trichostatin A (TSA), a histone deacetylase inhibitor in the p53-null human lung cancer cell line H1299. Ectopic expression of Sox4 led to the induction of PUMA expression at the mRNA and protein levels, and TSA-mediated up-regulation of PUMA transcription was repressed by the knockdown of Sox4. Using luciferase assays and chromatin immunoprecipitation, we also determined that Sox4 recruits p300 on the PUMA promoter region and increases PUMA gene expression in response to TSA treatment. Taken together, these results suggest that Sox4 is required for p53-independent apoptotic cell death mediated by PUMA induction via TSA treatment. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

A signaling role of histone-binding proteins and INHAT subunits pp32 and Set/TAF-Ibeta in integrating chromatin hypoacetylation and transcriptional repression.

PubMed

Kutney, Sara N; Hong, Rui; Macfarlan, Todd; Chakravarti, Debabrata

2004-07-16

Various post-translational modifications of histones significantly influence gene transcription. Although un- or hypoacetylated histones are tightly linked to transcriptional repression, the mechanisms and identities of chromatin signal transducer proteins integrating histone hypoacetylation into repression in humans have remained largely unknown. Here we show that the mammalian histone-binding proteins and inhibitor of acetyltransferases (INHAT) complex subunits, Set/template-activating factor-Ibeta (TAF-Ibeta) and pp32, specifically bind to unacetylated, hypoacetylated, and repressively marked histones but not to hyperacetylated histones. Additionally, Set/TAF-Ibeta and pp32 associate with histone deacetylases in vitro and in vivo and repress transcription from a chromatin-integrated template in vivo. Finally, Set/TAF-Ibeta and pp32 associate with an endogenous estrogen receptor-regulated gene, EB1, in the hypoacetylated transcriptionally inactive state but not with the hyperacetylated transcriptionally active form. Together, these data define a novel in vivo mechanistic role for the mammalian Set/TAF-Ibeta and pp32 proteins as transducers of chromatin signaling by integrating chromatin hypoacetylation and transcriptional repression.

Environmental and occupational risk factors for progressive supranuclear palsy: Case-control study.

PubMed

Litvan, Irene; Lees, Peter S J; Cunningham, Christopher R; Rai, Shesh N; Cambon, Alexander C; Standaert, David G; Marras, Connie; Juncos, Jorge; Riley, David; Reich, Stephen; Hall, Deborah; Kluger, Benzi; Bordelon, Yvette; Shprecher, David R

2016-05-01

The cause of progressive supranuclear palsy (PSP) is largely unknown. Based on evidence for impaired mitochondrial activity in PSP, we hypothesized that the disease may be related to exposure to environmental toxins, some of which are mitochondrial inhibitors. This multicenter case-control study included 284 incident PSP cases of 350 cases and 284 age-, sex-, and race-matched controls primarily from the same geographical areas. All subjects were administered standardized interviews to obtain data on demographics, residential history, and lifetime occupational history. An industrial hygienist and a toxicologist unaware of case status assessed occupational histories to estimate past exposure to metals, pesticides, organic solvents, and other chemicals. Cases and controls were similar on demographic factors. In unadjusted analyses, PSP was associated with lower education, lower income, more smoking pack-years, more years of drinking well water, more years living on a farm, more years living 1 mile from an agricultural region, more transportation jobs, and more jobs with exposure to metals in general. However, in adjusted models, only more years of drinking well water was significantly associated with PSP. There was an inverse association with having a college degree. We did not find evidence for a specific causative chemical exposure; higher number of years of drinking well water is a risk factor for PSP. This result remained significant after adjusting for income, smoking, education and occupational exposures. This is the first case-control study to demonstrate PSP is associated with environmental factors. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

Contribution of occupational factors to the incidence and persistence of chronic low back pain among workers: results from the longitudinal VISAT study.

PubMed

Esquirol, Yolande; Niezborala, Michel; Visentin, Monique; Leguevel, Anne; Gonzalez, Ignacio; Marquié, Jean-Claude

2017-03-01

Among the aetiological factors of chronic low back pain (CLBP), occupational factors are often suspected, but their contribution remains to be ascertained. This study aimed to determine the impact of a wide range of occupational factors on the incidence and persistence of CLBP. From the VISAT (VIeillissement SAnté Travail) study, 1560 workers were examined at baseline and 5 years later. CLBP was defined as having low back pain or specific treatment for at least 6 months. Participants newly affected with CLBP and those with persistent CLBP at follow-up were distinguished. In addition to individual factors, a broad panel of occupational factors were analysed, covering employment, physical, organisational and psychosocial factors. Multivariate analyses were used to determine predictive factors of incidence and persistence of CLBP. Receiver operating characteristic (ROC) curves were performed to analyse the contribution of occupational factors. 22.6% of participants without any CLBP initially presented with CLBP 5 years later, while 53.7% of participants with CLBP at baseline had CLBP at the second collection. Carrying heavy loads, the lack of recognition of completed work and productivity-related income predicted a higher risk of incidence of CLBP. However, no significant association between occupational factors and the risk for persistence of CLBP was observed, while the risk was multiplied by two for history of depression and rheumatological events. ROC curves confirmed the significant contribution of occupational factors to incidence of CLBP. Occupational factors played a pivotal role in the incidence of CLBP, while individual factors were the main determinants of persistence of CLBP. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Occupational risk factors for mycosis fungoides: a European multicenter case-control study.

PubMed

Morales-Suárez-Varela, Maria M; Olsen, Jorn; Johansen, Preben; Kaerlev, Linda; Guénel, Pascal; Arveux, Patrick; Wingren, Gun; Hardell, Lennart; Ahrens, Wolfgang; Stang, Andreas; Llopis, Agustin; Merletti, Franco; Aurrekoetxea, Juan Jose; Masala, Giovanna

2004-03-01

Mycosis fungoides (MF) is a rare disease with an unknown etiology. Its distribution suggests that occupational exposures may play a role. In the present study, we searched for occupational factors associated with MF. A European multicenter case-control study on seven rare cancers, including MF, was conducted from 1995 to 1997. Patients between 35 and 69 years of age diagnosed with MF (n = 134) were identified and their diagnoses were checked by a reference pathologist who classified 83 cases as definitive, 35 cases as possible, and 16 cases as not histologically verified. Of the 118 histologically verified cases, 104 were interviewed, of which 76 were definitive cases. As controls, we selected population controls and colon cancer controls to serve all seven case groups. Altogether, 833 colon cancer controls and 2071 population controls were interviewed. The response rate was 91.5% for cases (76 of the 83 definitive cases), and 66.6% for controls. A high risk of MF for men was observed in the industries of other non-metallic mineral products (Odds Ratio [OR] 5.3, 95% confidence interval [CI] = 1.7-16.2) and of wholesale trade (OR 3.6, 95% CI = 1.3-10.5). A high risk was found for female employees in the sector of pulp paper manufacture (OR 14.4, 95% CI = 2.2-95.1). The male occupations with the highest risks were glass formers, potters, and ceramics workers (OR 17.9, 95% CI = 5.4-59.4) and technical salesmen (OR 8.6, 95% CI = 2.4-30.8). For women, the occupations associated with the highest risks were government executives (OR 4.8, 95% CI = 1.0-22.6) and railway and road vehicles loaders (OR 3.9, 95% CI = 1.0-14.0). The results suggest that some occupational factors are associated with MF. Working as glass formers, pottery, and ceramics workers carried the highest risk, and these findings deserve further attention and replication. Females working in the paper and pulp industries may also be exposed to carcinogens of relevance to MF.

Spinal injury in car crashes: crash factors and the effects of occupant age.

PubMed

Bilston, Lynne E; Clarke, Elizabeth C; Brown, Julie

2011-08-01

Motor vehicle crashes are the leading cause of serious spinal injury in most developed nations. However, since these injuries are rare, systematic analyses of the crash factors that are predictive of spinal injury have rarely been performed. This study aimed to use a population-reference crash sample to identify crash factors associated with moderate to severe spinal injury, and how these vary with occupant age. The US National Automotive Sampling System Crashworthiness Data System (NASS) data for 1993-2007 were analysed using logistic regression to identify crash factors associated with Abbreviated Injury Scale (AIS)2+ spinal injury among restrained vehicle passengers. Risk of moderate or severe spinal injury (AIS2+) was associated with higher severity crashes (OR=3.5 (95% CI 2.6 to 4.6)), intrusion into an occupant's seating position (OR=2.7 (95% CI 1.9 to 3.7)), striking a fixed object rather than another car (OR=1.7 (95% CI 1.3 to 2.1)), and use of a shoulder-only belt (OR=2.7 (95% CI 1.5 to 4.8)). Older occupants (65 years or older) were at higher risk of spinal injury than younger adults in frontal, side and rollover crashes. Children under 16 were at a lower risk of spinal injury than adults in all crash types except frontal crashes. While the risk of serious spinal injury in motor vehicle crashes is low, these injuries are more common in crashes of higher severity or into fixed objects, and in the presence of intrusion. There are elevated risks of spinal injury for older occupants compared with younger adults, which may reflect changes in biomechanical tolerances with age. Children appear to be at lower risk of serious spinal injury than adults except in frontal crashes.

Histone modifier gene mutations in peripheral T-cell lymphoma not otherwise specified.

PubMed

Ji, Meng-Meng; Huang, Yao-Hui; Huang, Jin-Yan; Wang, Zhao-Fu; Fu, Di; Liu, Han; Liu, Feng; Leboeuf, Christophe; Wang, Li; Ye, Jing; Lu, Yi-Ming; Janin, Anne; Cheng, Shu; Zhao, Wei-Li

2018-04-01

Due to heterogeneous morphological and immunophenotypic features, approximately 50% of peripheral T-cell lymphomas are unclassifiable and categorized as peripheral T-cell lymphomas, not otherwise specified. These conditions have an aggressive course and poor clinical outcome. Identification of actionable biomarkers is urgently needed to develop better therapeutic strategies. Epigenetic alterations play a crucial role in tumor progression. Histone modifications, particularly methylation and acetylation, are generally involved in chromatin state regulation. Here we screened the core set of genes related to histone methylation ( KMT2D , SETD2 , KMT2A , KDM6A ) and acetylation ( EP300 , CREBBP ) and identified 59 somatic mutations in 45 of 125 (36.0%) patients with peripheral T-cell lymphomas, not otherwise specified. Histone modifier gene mutations were associated with inferior progression-free survival time of the patients, irrespective of chemotherapy regimens, but an increased response to the histone deacetylase inhibitor chidamide. In vitro , chidamide significantly inhibited the growth of EP300-mutated T-lymphoma cells and KMT2D-mutated T-lymphoma cells when combined with the hypomethylating agent decitabine. Mechanistically, decitabine acted synergistically with chidamide to enhance the interaction of KMT2D with transcription factor PU.1, regulated H3K4me-associated signaling pathways, and sensitized T-lymphoma cells to chidamide. In a xenograft KMT2D-mutated T-lymphoma model, dual treatment with chidamide and decitabine significantly retarded tumor growth and induced cell apoptosis through modulation of the KMT2D/H3K4me axis. Our work thus contributes to the understanding of aberrant histone modification in peripheral T-cell lymphomas, not otherwise specified and the stratification of a biological subset that can benefit from epigenetic treatment. Copyright© 2018 Ferrata Storti Foundation.

Med5(Nut1) and Med17(Srb4) Are Direct Targets of Mediator Histone H4 Tail Interactions

PubMed Central

Liu, Zhongle; Myers, Lawrence C.

2012-01-01

The Mediator complex transmits activation signals from DNA bound transcription factors to the core transcription machinery. In addition to its canonical role in transcriptional activation, recent studies have demonstrated that S. cerevisiae Mediator can interact directly with nucleosomes, and their histone tails. Mutations in Mediator subunits have shown that Mediator and certain chromatin structures mutually impact each other structurally and functionally in vivo. We have taken a UV photo cross-linking approach to further delineate the molecular basis of Mediator chromatin interactions and help determine whether the impact of certain Mediator mutants on chromatin is direct. Specifically, by using histone tail peptides substituted with an amino acid analog that is a UV activatible crosslinker, we have identified specific subunits within Mediator that participate in histone tail interactions. Using Mediator purified from mutant yeast strains we have evaluated the impact of these subunits on histone tail binding. This analysis has identified the Med5 subunit of Mediator as a target for histone tail interactions and suggests that the previously observed effect of med5 mutations on telomeric heterochromatin and silencing is direct. PMID:22693636

Drosophila histone locus bodies form by hierarchical recruitment of components

PubMed Central

White, Anne E.; Burch, Brandon D.; Yang, Xiao-cui; Gasdaska, Pamela Y.; Dominski, Zbigniew; Marzluff, William F.

2011-01-01

Nuclear bodies are protein- and RNA-containing structures that participate in a wide range of processes critical to genome function. Molecular self-organization is thought to drive nuclear body formation, but whether this occurs stochastically or via an ordered, hierarchical process is not fully understood. We addressed this question using RNAi and proteomic approaches in Drosophila melanogaster to identify and characterize novel components of the histone locus body (HLB), a nuclear body involved in the expression of replication-dependent histone genes. We identified the transcription elongation factor suppressor of Ty 6 (Spt6) and a homologue of mammalian nuclear protein of the ataxia telangiectasia–mutated locus that is encoded by the homeotic gene multisex combs (mxc) as novel HLB components. By combining genetic manipulation in both cell culture and embryos with cytological observations of Mxc, Spt6, and the known HLB components, FLICE-associated huge protein, Mute, U7 small nuclear ribonucleoprotein, and MPM-2 phosphoepitope, we demonstrated sequential recruitment and hierarchical dependency for localization of factors to HLBs during development, suggesting that ordered assembly can play a role in nuclear body formation. PMID:21576393

Influence of Arsenic on Global Levels of Histone Posttranslational Modifications: a Review of the Literature and Challenges in the Field.

PubMed

Howe, Caitlin G; Gamble, Mary V

2016-09-01

Arsenic is a human carcinogen and also increases the risk for non-cancer outcomes. Arsenic-induced epigenetic dysregulation may contribute to arsenic toxicity. Although there are several reviews on arsenic and epigenetics, these have largely focused on DNA methylation. Here, we review investigations of the effects of arsenic on global levels of histone posttranslational modifications (PTMs). Multiple studies have observed that arsenic induces higher levels of H3 lysine 9 dimethylation (H3K9me2) and also higher levels of H3 serine 10 phosphorylation (H3S10ph), which regulate chromosome segregation. In contrast, arsenic causes a global loss of H4K16ac, a histone PTM that is a hallmark of human cancers. Although the findings for other histone PTMs have not been entirely consistent across studies, we discuss biological factors which may contribute to these inconsistencies, including differences in the dose, duration, and type of arsenic species examined; the tissue or cell line evaluated; differences by sex; and exposure timing. We also discuss two important considerations for the measurement of histone PTMs: proteolytic cleavage of histones and arsenic-induced alterations in histone expression.

Occupational factors and subsequent major depressive and generalized anxiety disorders in the prospective French national SIP study.

PubMed

Niedhammer, Isabelle; Malard, Lucile; Chastang, Jean-François

2015-02-28

The literature has been extensive on the associations between psychosocial work factors and mental health. Nevertheless, the studies using prospective design, various concepts and more than one measurement point in time for these factors and diagnostic interview to assess mental disorders remain seldom in the literature. This study is an attempt to fill the gap in this topic. The study was based on a national representative sample of 4717 workers of the French working population (SIP survey), interviewed in 2006 and reinterviewed again in 2010 and free of mental disorders at baseline. Psychosocial work factors, measured in both 2006 and 2010, included: psychological demands, decision latitude, social support, reward, emotional demands, role conflict, ethical conflict, tensions with the public, job insecurity and work-life imbalance. Other occupational factors related to working time/hours and physical work environment were also studied. Major depressive (MDD) and generalized anxiety disorders (GAD) were measured using a standardised diagnostic interview (MINI). Covariates were age, occupation, marital status, having a child under 3 y, social support outside work and stressful life events. Multivariate analyses were performed using weighted logistic regression models. Using models taking all occupational factors into account simultaneously, low reward and job insecurity predicted MDD. Psychological demands, low reward, emotional demands and job insecurity were predictive of GAD. The more frequent the exposure to job insecurity, the higher the risk of MDD and GAD, and the more frequent the exposure to psychological demands and low reward, the higher the risk of GAD. No effect was observed for repeated exposure to occupational factors. Classical and emergent psychosocial work factors were predictive factors of depression and anxiety with dose-response associations in terms of frequency of exposure. More attention may be needed on emergent psychosocial work factors and

Structural Basis for the Histone Chaperone Activity of Asf1

PubMed Central

English, Christine M.; Adkins, Melissa W.; Carson, Joshua J.; Churchill, Mair E.A.; Tyler, Jessica K.

2010-01-01

SUMMARY Asf1 is a highly conserved chaperone of histones H3/H4 that assembles or disassembles chromatin during transcription, replication, and repair. The structure of the globular domain of Asf1 bound to H3/H4 determined by X-ray crystallography to a resolution of 1.7 Å shows how Asf1 binds the H3/H4 heterodimer, enveloping the C-terminus of histone H3 and physically blocking formation of the H3/H4 heterotetramer. Unexpectedly, the C-terminus of histone H4 that forms a mini-beta sheet with histone H2A in the nucleosome, undergoes a major conformational change upon binding to Asf1 and adds a beta strand to the Asf1 beta-sheet sandwich. Interactions with both H3 and H4 were required for Asf1 histone chaperone function in vivo and in vitro. The Asf1-H3/H4 structure suggests a “strand-capture” mechanism whereby the H4 tail acts as a lever to facilitate chromatin disassembly / assembly that may be used ubiquitously by histone chaperones. PMID:17081973

CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum

PubMed Central

Levine, Amir A.; Guan, Zhonghui; Barco, Angel; Xu, Shiqin; Kandel, Eric R.; Schwartz, James H.

2005-01-01

Remodeling chromatin is essential for cAMP-regulated gene expression, necessary not only for development but also for memory storage and other enduring mental states. Histone acetylation and deacetylation mediate long-lasting forms of synaptic plasticity in Aplysia as well as cognition in mice. Here, we show that histone acetylation by the cAMP-response element binding protein (CREB)-binding protein (CBP) mediates sensitivity to cocaine by regulating expression of the fosB gene and its splice variant, ΔfosB, a transcription factor previously implicated in addiction. Using the chromatin immunoprecipitation assay with antibodies against histone H4 or CBP, we find that CBP is recruited to the fosB promoter to acetylate histone H4 in response to acute exposure to cocaine. We show that mutant mice that lack one allele of the CBP gene and have normal levels of fosB expression are less sensitive to chronic (10-day) administration of cocaine than are wild-type mice. This decreased sensitivity is correlated with decreased histone acetylation and results in decreased fosB expression and diminished accumulation of ΔfosB. Thus, CBP, which forms part of the promoter complex with CREB, mediates sensitivity to cocaine by acetylating histones. PMID:16380431

Environmental and psychosocial factors affecting seat belt use among Turkish front-seat occupants in Ankara: two observation studies.

PubMed

Simşekoğlu, Ozlem; Lajunen, Timo

2008-01-01

Low seat belt use rate among car occupants is one of the main problems contributing to low driver and passenger safety in Turkey, where injury and fatality rates of car occupants are very high in traffic crashes. The present article consists of two observation studies, which were conducted in Ankara. The first study aimed at investigating environmental factors and occupant characteristics affecting seat belt use among front-seat occupants, and the objective of the second study was to investigate the relationship between driver and front-seat passenger seat belt use. In the first study, 4, 227 front-seat occupants (drivers or front seat passengers) were observed on four different road sides and, in the second study 1, 398 front seat occupants were observed in car parks of five different shopping centers in Ankara. In both observations, front-seat occupants' seat bet use (yes, no), sex (male, female), and age (< 30 years, 30-50 years, > 50 years) were recorded. The data were analyzed using chi-square statistics and binary logistic regression techniques. Results of the first study showed that seat belt use proportion among observed front seat occupants was very low (25%). Being female and traveling on intercity roads were two main factors positively related to use a seat belt among front-seat occupants. High correlations between seat belt use of the drivers and front-seat passengers were found in the second study. Overall, low seat belt use rate (25%) among the front-seat occupants should be increased urgently for an improved driver and passenger safety in Turkey. Seat belt campaigns especially tailored for male front-seat occupants and for the front-seat occupants traveling on city roads are needed to increase seat belt use rates among them. Also, both drivers and passengers may have an important role in enforcing seat belt use among themselves.

Linker histone H1.0 interacts with an extensive network of proteins found in the nucleolus

PubMed Central

Kalashnikova, Anna A.; Winkler, Duane D.; McBryant, Steven J.; Henderson, Ryan K.; Herman, Jacob A.; DeLuca, Jennifer G.; Luger, Karolin; Prenni, Jessica E.; Hansen, Jeffrey C.

2013-01-01

The H1 linker histones are abundant chromatin-associated DNA-binding proteins. Recent evidence suggests that linker histones also may function through protein–protein interactions. To gain a better understanding of the scope of linker histone involvement in protein–protein interactions, we used a proteomics approach to identify H1-binding proteins in human nuclear extracts. Full-length H1.0 and H1.0 lacking its C-terminal domain (CTD) were used for protein pull-downs. A total of 107 candidate H1.0 binding proteins were identified by LC-MS/MS. About one-third of the H1.0-dependent interactions were mediated by the CTD, and two-thirds by the N-terminal domain-globular domain fragment. Many of the proteins pulled down by H1.0 were core splicing factors. Another group of H1-binding proteins functions in rRNA biogenesis. H1.0 also pulled down numerous ribosomal proteins and proteins involved in cellular transport. Strikingly, nearly all of the H1.0-binding proteins are found in the nucleolus. Quantitative biophysical studies with recombinant proteins confirmed that H1.0 directly binds to FACT and the splicing factors SF2/ASF and U2AF65. Our results demonstrate that H1.0 interacts with an extensive network of proteins that function in RNA metabolism in the nucleolus, and suggest that a new paradigm for linker histone action is in order. PMID:23435226

Predictors for return to work for those with occupational respiratory disease: clinical and structural factors.

PubMed

Zoeckler, Jeanette M; Cibula, Donald A; Morley, Christopher P; Lax, Michael B

2013-12-01

Few occupational researchers have examined "return to work" among patients with work-related respiratory diseases. In addition, prior studies have emphasized individual patient characteristics rather than a more multi-dimensional approach that includes both clinical and structural factors. A retrospective chart review identified patients with occupational respiratory diseases in the Occupational Health Clinical Center, Syracuse, NY between 1991 and 2009. We assessed predictors of work status using an exploratory, sequential mixed methods research design, multinomial (n = 188) and Cox regressions (n = 130). The findings suggest that patients with an increased number of diagnoses, non-union members, and those who took more than a year before clinical presentation had significantly poorer work status outcomes, after adjusting for age, education level, and relevant diagnoses. Efforts to prevent slow return to work after developing occupational respiratory disease should recognize the importance of timely access to occupational health services, disease severity, union membership, and smoking status. © 2013 Wiley Periodicals, Inc.

Highly acidic C-terminal domain of pp32 is required for the interaction with histone chaperone, TAF-Ibeta.

PubMed

Lee, In-Seon; Oh, Sang-Min; Kim, Sung-Mi; Lee, Dong-Seok; Seo, Sang-Beom

2006-12-01

We have previously reported that INHAT (inhibitor of acetyltransferases) complex subunits, TAF (template activating factor)-Ialpha, TAF-Ibeta and pp32 can inhibit histone acetylation and HAT (histone acetyltransferase)-dependent transcription by binding to histones. Evidences are accumulating that INHAT complex subunits have important regulatory roles in various cellular activities such as replication, transcription, and apoptosis etc. However, how these subunits interact each other remains largely unknown. Using immunoprecipitation (IP) and protein-protein interaction assays with TAF-Ibeta and pp32 deletion mutant proteins, we identify INHAT complex subunits, TAF-Ibeta and pp32 interaction requires highly acidic C-terminal domain of pp32. We also show that the interaction between the INHAT complex subunits is stronger in the presence of histones. In this study, we report that the synergistic inhibition of HAT-mediated transcription by TAF-Ibeta and pp32 is dependent on the highly acidic C-terminal domain of pp32.

Biphasic Incorporation of Centromeric Histone CENP-A in Fission Yeast

PubMed Central

Takayama, Yuko; Sato, Hiroshi; Saitoh, Shigeaki; Ogiyama, Yuki; Masuda, Fumie

2008-01-01

CENP-A is a centromere-specific histone H3 variant that is essential for kinetochore formation. Here, we report that the fission yeast Schizosaccharomyces pombe has at least two distinct CENP-A deposition phases across the cell cycle: S and G2. The S phase deposition requires Ams2 GATA factor, which promotes histone gene activation. In Δams2, CENP-A fails to retain during S, but it reaccumulates onto centromeres via the G2 deposition pathway, which is down-regulated by Hip1, a homologue of HIRA histone chaperon. Reducing the length of G2 in Δams2 results in failure of CENP-A accumulation, leading to chromosome missegregation. N-terminal green fluorescent protein-tagging reduces the centromeric association of CENP-A, causing cell death in Δams2 but not in wild-type cells, suggesting that the N-terminal tail of CENP-A may play a pivotal role in the formation of centromeric nucleosomes at G2. These observations imply that CENP-A is normally localized to centromeres in S phase in an Ams2-dependent manner and that the G2 pathway may salvage CENP-A assembly to promote genome stability. The flexibility of CENP-A incorporation during the cell cycle may account for the plasticity of kinetochore formation when the authentic centromere is damaged. PMID:18077559

EPC1/TIP60-Mediated Histone Acetylation Facilitates Spermiogenesis in Mice.

PubMed

Dong, Yixin; Isono, Kyo-Ichi; Ohbo, Kazuyuki; Endo, Takaho A; Ohara, Osamu; Maekawa, Mamiko; Toyama, Yoshiro; Ito, Chizuru; Toshimori, Kiyotaka; Helin, Kristian; Ogonuki, Narumi; Inoue, Kimiko; Ogura, Atsuo; Yamagata, Kazutsune; Kitabayashi, Issay; Koseki, Haruhiko

2017-10-01

Global histone hyperacetylation is suggested to play a critical role for replacement of histones by transition proteins and protamines to compact the genome during spermiogenesis. However, the underlying mechanisms for hyperacetylation-mediated histone replacement remains poorly understood. Here, we report that EPC1 and TIP60, two critical components of the mammalian nucleosome acetyltransferase of H4 (NuA4) complexes, are coexpressed in male germ cells. Strikingly, genetic ablation of either Epc1 or Tip60 disrupts hyperacetylation and impairs histone replacement, in turn causing aberrant spermatid development. Taking these observations together, we reveal an essential role of the NuA4 complexes for histone hyperacetylation and subsequent compaction of the spermatid genome. Copyright © 2017 American Society for Microbiology.

Histone underacetylation is an ancient component of mammalian X chromosome inactivation

PubMed Central

Wakefield, Matthew J.; Keohane, Ann M.; Turner, Bryan M.; Graves, Jennifer A. Marshall

1997-01-01

Underacetylation of histone H4 is thought to be involved in the molecular mechanism of mammalian X chromosome inactivation, which is an important model system for large-scale genetic control in eukaryotes. However, it has not been established whether histone underacetylation plays a critical role in the multistep inactivation pathway. Here we demonstrate differential histone H4 acetylation between the X chromosomes of a female marsupial, Macropus eugenii. Histone underacetylation is the only molecular aspect of X inactivation known to be shared by marsupial and eutherian mammals. Its strong evolutionary conservation implies that, unlike DNA methylation, histone underacetylation was a feature of dosage compensation in a common mammalian ancestor, and is therefore likely to play a central role in X chromosome inactivation in all mammals. PMID:9275180

Cross-sectional associations between occupational factors and musculoskeletal pain in women teachers, nurses and sonographers.

PubMed

Arvidsson, Inger; Gremark Simonsen, Jenny; Dahlqvist, Camilla; Axmon, Anna; Karlson, Björn; Björk, Jonas; Nordander, Catarina

2016-01-18

It is usually assumed that musculoskeletal pain is associated with both the physical workload and the psychosocial work environment, as well as with personal and lifestyle factors. This study aims to ascertain the prevalence of musculoskeletal pain in women with varying or different occupational exposures, and to explore the associations between musculoskeletal pain and the occupational and personal factors. A questionnaire on physical, psychosocial and individual factors was answered by 1591 women in five occupational groups with contrasting occupational exposures (teachers, anaesthetic, theatre, and assistant nurses, and sonographers). The outcome measure was musculoskeletal pain (in a new model based on frequency and intensity of complaints the preceding year) from the neck, shoulders, hands, lower back and feet. Neck pain was equally frequent among teachers, assistant nurses and sonographers, and less frequent in anaesthetic and theatre nurses. The sonographers experienced the highest prevalence of shoulder pain, while the assistant nurses were the most affected in the wrists and hands, lower back, and feet. The teachers reported the highest scores in most of the psychosocial dimensions. The theatre nurses scored highest in strenuous work postures and movements (mechanical exposure index, MEI), and the assistant nurses in physical activity and lifting (physical exposure index, PHYI). Multivariable models in the total population showed that both the physical workload and the psychosocial work environment were associated with pain in all body regions, though different factors affected different regions. Pain in the neck, shoulders, hands and lower back was strongly associated with a high MEI and high job demands, while pain in the feet was associated with a high PHYI and a high BMI. A young age was associated with pain in the neck, and an older age was associated with pain in the hands and feet. Lack of time for personal recovery was associated with pain in the

Phosphatase Rtr1 Regulates Global Levels of Serine 5 RNA Polymerase II C-Terminal Domain Phosphorylation and Cotranscriptional Histone Methylation.

PubMed

Hunter, Gerald O; Fox, Melanie J; Smith-Kinnaman, Whitney R; Gogol, Madelaine; Fleharty, Brian; Mosley, Amber L

2016-09-01

In eukaryotes, the C-terminal domain (CTD) of Rpb1 contains a heptapeptide repeat sequence of (Y1S2P3T4S5P6S7)n that undergoes reversible phosphorylation through the opposing action of kinases and phosphatases. Rtr1 is a conserved protein that colocalizes with RNA polymerase II (RNAPII) and has been shown to be important for the transition from elongation to termination during transcription by removing RNAPII CTD serine 5 phosphorylation (Ser5-P) at a selection of target genes. In this study, we show that Rtr1 is a global regulator of the CTD code with deletion of RTR1 causing genome-wide changes in Ser5-P CTD phosphorylation and cotranscriptional histone H3 lysine 36 trimethylation (H3K36me3). Using chromatin immunoprecipitation and high-resolution microarrays, we show that RTR1 deletion results in global changes in RNAPII Ser5-P levels on genes with different lengths and transcription rates consistent with its role as a CTD phosphatase. Although Ser5-P levels increase, the overall occupancy of RNAPII either decreases or stays the same in the absence of RTR1 Additionally, the loss of Rtr1 in vivo leads to increases in H3K36me3 levels genome-wide, while total histone H3 levels remain relatively constant within coding regions. Overall, these findings suggest that Rtr1 regulates H3K36me3 levels through changes in the number of binding sites for the histone methyltransferase Set2, thereby influencing both the CTD and histone codes. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Sitting occupations are an independent risk factor for Ischemic stroke in North Indian population.

PubMed

Kumar, A; Prasad, M; Kathuria, P

2014-10-01

Stroke is a multi-factorial disease and is influenced by complex environmental interactions. The purpose of this case-control study was to determine the relationship of sitting occupations with ischemic stroke in the North Indian population. In a hospital-based case-control study, age- and sex-matched controls were recruited from the outpatient department and the neurology ward of All India Institute of Medical Sciences, New Delhi. Occupation along with other demographic and risk factor variables was measured in-person interview in standardized case record form. The multivariate logistic regression model was used to estimate the odds ratio associated with ischemic stroke. Two hundred and twenty-four people post-stroke and 224 control participants were recruited from the period of February 2009 to February 2012. Mean age of cases and controls was 53.47 ± 14 and 52.92 ± 13.4, respectively. The occupations which involve sitting at work were independently associated with the risk of ischemic stroke after adjustment for demographic and risk factor variables (OR 2.2, 95% CI 1.12-3.8). The result of this study has shown an independent association between the sitting occupations and ischemic stroke in North Indian population. The present study supports the workplace health initiative to implement workplace physical activity policy and encourages employee to reduce the amount of time they spend sitting throughout the day.

Influence of occupational factors on regional differences in sick leave: A prospective population study.

PubMed

Sterud, Tom; Johannessen, Håkon A

2018-05-01

Number of sick leave days vary by county, but little is known about the extent to which this gradient may be explained by differences pertaining to occupational composition and occupational exposure. A randomly drawn cohort from the general population in Norway, aged 18-69 years, was interviewed by telephone in the second half of 2009 ( n=12,255; response at baseline=60.9%) and followed up in national registries to the end of 2010. Eligible respondents were registered with an active employee relationship in 2009 and 2010 ( n=8275). Information on counties ( n=19) was based on the administrative register. The outcome of interest was the number of physician-certified sick-leave days divided by scheduled man-days during 2010 (i.e. sick-leave percentage (SLP)). The average SLP during 2010 was 5.2%. The between-county variation in SLP ranged from 4.0% to 7.2%. Compared to the age- and gender-adjusted model, adjustment for occupation, economic sector and self-reported occupational exposure reduced the median difference in SLP between the county with the lowest SLP (reference county) and the SLP in the other counties by 1.08 percentage points (i.e. a 58% reduction). The impact of occupational composition and occupational exposure on the total between-county variance in SLP was a 16% reduction. Occupational composition and self-reported occupational exposure help to explain a significant part of the difference in SLP between counties, and appear to be more important explanatory factors than demographic variables, self-reported health and smoking.

Targeting Histone Deacetylases in Diseases: Where Are We?

PubMed Central

Benedetti, Rosaria; Conte, Mariarosaria

2015-01-01

Abstract Significance: Epigenetic inactivation of pivotal genes involved in cell growth is a hallmark of human pathologies, in particular cancer. Histone acetylation balance obtained through opposing actions of histone deacetylases (HDACs) and histone acetyltransferases is one epigenetic mechanism controlling gene expression and is, thus, associated with disease etiology and progression. Interfering pharmacologically with HDAC activity can correct abnormalities in cell proliferation, migration, vascularization, and death. Recent Advances: Histone deacetylase inhibitors (HDACi) represent a new class of cytostatic agents that interfere with the function of HDACs and are able to increase gene expression by indirectly inducing histone acetylation. Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently being used in clinical trials for solid and hematological malignancies, and are, thus, promising candidates for cancer therapy. Critical Issues: (i) Non-specific (off-target) HDACi effects due to activities unassociated with HDAC inhibition. (ii) Advantages/disadvantages of non-selective or isoform-directed HDACi. (iii) Limited number of response-predictive biomarkers. (iv) Toxicity leading to dysfunction of critical biological processes. Future Directions: Selective HDACi could achieve enhanced clinical utility by reducing or eliminating the serious side effects associated with current first-generation non-selective HDACi. Isoform-selective and pan-HDACi candidates might benefit from the identification of biomarkers, enabling better patient stratification and prediction of response to treatment. Antioxid. Redox Signal. 23, 99–126. PMID:24382114

Histone H3 Lysine Methylation in Cognition and Intellectual Disability Disorders

ERIC Educational Resources Information Center

Parkel, Sven; Lopez-Atalaya, Jose P.; Barco, Angel

2013-01-01

Recent research indicates that epigenetic mechanisms and, in particular, the post-translational modification (PTM) of histones may contribute to memory encoding and storage. Among the dozens of possible histone PTMs, the methylation/demethylation of lysines in the N-terminal tail of histone H3 exhibits particularly strong links with cognitive…

Does an advantageous occupational position make women happier in contemporary Japan? Findings from the Japanese Study of Health, Occupation, and Psychosocial Factors Related Equity (J-HOPE).

PubMed

Umeda, Maki; McMunn, Anne; Cable, Noriko; Hashimoto, Hideki; Kawakami, Norito; Marmot, Michael

2015-12-01

Occupational position is one of the determinants of psychological health, but this association may differ for men and women depending on the social context. In contemporary Japanese society, occupational gender segregation persists despite increased numbers of women participating in the labour market, which may contribute to gender specific patterns in the prevalence of poor psychological health. The present study examined gender specific associations between occupational position and psychological health in Japan, and the potential mediating effects of job control and effort-reward imbalance in these associations. We used data obtained from 7123 men and 2222 women, aged between 18 and 65 years, who participated in an occupational cohort study, the Japanese Study of Health, Occupation, and Psychosocial Factors Related Equity (J-HOPE), between 2011 and 2012. We used logistic regression to examine the association between occupational position and poor psychological health, adjusted for age, working hours, household income and education, as well as psychosocial work characteristics (job control and effort-reward imbalance). The prevalence of poor psychological health increased from manual/service occupations (23%) to professionals/managers (38%) among women, while it did not vary by occupational position among men. In women, the significant association between occupational position and psychological health was not explained by job control, but was attenuated by effort-reward imbalance. Our findings suggest that Japanese women in more advantaged occupational positions are likely to be at a greater risk for poor psychological health due to higher levels of effort-reward imbalance at work.

Structural Investigations of the Nickel-Induced Inhibition of Truncated Constructs of the JMJD2 Family of Histone Demethylases Using X-ray Absorption Spectroscopy

PubMed Central

Giri, Nitai Charan; Passantino, Lisa; Sun, Hong; Zoroddu, Maria Antonietta; Costa, Max; Maroney, Michael J.

2013-01-01

Occupational and/or environmental exposure to nickel has been implicated in various types of cancer, and in vitro exposure to nickel compounds results in accumulation of Ni(II) ions in cells. One of the major targets of Ni(II) ions inside the cell is Fe(II)- and αKG-dependent dioxygenases. Using JMJD2A and JMJD2C as examples, we show that JMJD2 family of histone demethylases, which are products of putative oncogenes as well as Fe(II)- and αKG-dependent dioxygenases, are highly sensitive to inhibition by Ni(II) ions. In this work, X-ray absorption spectroscopy (XAS) has been used to investigate the Fe(II) active site of truncated JMJD2A and JMJD2C (1 – 350 aa) in the presence and absence of αKG and/or substrate to obtain mechanistic details of the early steps in catalysis that precede O2 binding in histone demethylation by the JMJD2 family of histone demethylases. Zinc K-edge XAS has been performed on the resting JMJD2A (with iron in the active site) to confirm the presence of the expected structural zinc site. XAS of the Ni(II)-substituted enzymes has also been performed to investigate the inhibition of these enzymes by Ni(II) ions. Our XAS results indicate that the five-coordinate Fe(II) center in the resting enzyme is retained in the binary and ternary complexes. In contrast, the Ni(II) center is six-coordinate in the resting enzyme, binary and ternary complexes. XAS results indicate that both Fe(II) and Ni(II) bind αKG in the binary and ternary complexes. The electron density build-up that is observed at the Fe(II) center in the presence of αKG and substrate is not observed at the Ni(II) center. Thus, both electronic and steric factors are responsible for Ni-induced inhibition of the JMJD2 family of histone demethylases. Ni-induced inhibition of these enzymes may explain the alteration of the epigenetic mechanism of gene expression that is responsible for Ni-induced carcinogenesis. PMID:23692052

The association between occupational factors and adverse health outcomes in chronic obstructive pulmonary disease

PubMed Central

Blanc, P; Eisner, M; Trupin, L; Yelin, E; Katz, P; Balmes, J

2004-01-01

Background and Aims: Despite recognition that occupational exposures may make a substantive contribution to the aetiology of COPD, little is known about the potential role of work related factors in COPD related health outcomes. Methods: Prospective cohort study using structured telephone interviews among a random sample of adults aged 55–75 reporting a COPD condition (emphysema, chronic bronchitis, or COPD). Using multivariate models adjusting for smoking and demographic factors, the separate and combined associations were estimated between occupational exposure to vapours, gas, dust, or fumes (VGDF) and leaving work due to lung disease (respiratory related work disability) with health outcomes and utilisation ascertained at one year follow up. Results: Of 234 subjects, 128 (55%) reported exposure to VGDF on their longest held jobs, 58 (25%) reported respiratory related work disability, and 38 (16%) subjects reported both. Combined exposure to VGDF and respiratory related work disability (rather than either factor alone) was associated with the greatest risk at follow up of frequent (everyday) restricted activity days attributed to a breathing or lung condition (OR 3.8; 95% CI 1.4 to 10.1), emergency department (ED) visit (OR 3.9; 95% CI 1.4 to 10.5), and hospitalisation (OR 7.6; 95% CI 1.8 to 32). Conclusions: Among persons with COPD, past occupational exposures and work disability attributed to lung disease, particularly in combination, appear to be risk factors for adverse health related outcomes. PMID:15258271

Disability pension by occupational class - the impact of work-related factors: The Hordaland Health Study Cohort

PubMed Central

2011-01-01

Background The social gradient in disability pension is well recognized, however mechanisms accounting for the gradient are largely unknown. The aim of this study was to examine the association between occupational class and subsequent disability pension among middle-aged men and women, and to what extent work-related factors accounted for the association. Methods A subsample (N = 7031) of the population-based Hordaland Health Study (HUSK) conducted in 1997-99, provided self-reported information on health and work-related factors, and were grouped in four strata by Erikson, Goldthorpe and Portocareros occupational class scheme. The authors obtained follow-up data on disability pension by linking the health survey to national registries of benefit (FD-trygd). They employed Cox regression analysis and adjusted for gender, health (medical conditions, mental health, self-perceived health, somatic symptoms) and work-related factors (working hours, years in current occupation, physical demands, job demands, job control). Results A strong gradient in disability pension by occupational class was found. In the fully adjusted model the risk (hazard ratio) ranged from 1.41 (95% CI 0.84 to 2.33) in the routine non-manual class, 1.87 (95% CI 1.07 to 3.27) in the skilled manual class and 2.12 (95% CI 1.14 to 3.95) in the unskilled manual class, employing the administrator and professional class as reference. In the gender and health-adjusted model work-related factors mediated the impact of occupational class on subsequent disability pension with 5% in the routine non-manual class, 26% in the skilled manual class and 24% in the unskilled manual class. The impact of job control and physical demands was modest, and mainly seen among skilled and unskilled manual workers. Conclusions Workers in the skilled and unskilled manual classes had a substantial unexplained risk of disability pension. Work-related factors only had a moderate impact on the disability risk. Literature indicates

Disability pension by occupational class--the impact of work-related factors: the Hordaland Health Study Cohort.

PubMed

Haukenes, Inger; Mykletun, Arnstein; Knudsen, Ann Kristin; Hansen, Hans-Tore; Mæland, John Gunnar

2011-05-30

The social gradient in disability pension is well recognized, however mechanisms accounting for the gradient are largely unknown. The aim of this study was to examine the association between occupational class and subsequent disability pension among middle-aged men and women, and to what extent work-related factors accounted for the association. A subsample (N = 7031) of the population-based Hordaland Health Study (HUSK) conducted in 1997-99, provided self-reported information on health and work-related factors, and were grouped in four strata by Erikson, Goldthorpe and Portocareros occupational class scheme. The authors obtained follow-up data on disability pension by linking the health survey to national registries of benefit (FD-trygd). They employed Cox regression analysis and adjusted for gender, health (medical conditions, mental health, self-perceived health, somatic symptoms) and work-related factors (working hours, years in current occupation, physical demands, job demands, job control). A strong gradient in disability pension by occupational class was found. In the fully adjusted model the risk (hazard ratio) ranged from 1.41 (95% CI 0.84 to 2.33) in the routine non-manual class, 1.87 (95% CI 1.07 to 3.27) in the skilled manual class and 2.12 (95% CI 1.14 to 3.95) in the unskilled manual class, employing the administrator and professional class as reference. In the gender and health-adjusted model work-related factors mediated the impact of occupational class on subsequent disability pension with 5% in the routine non-manual class, 26% in the skilled manual class and 24% in the unskilled manual class. The impact of job control and physical demands was modest, and mainly seen among skilled and unskilled manual workers. Workers in the skilled and unskilled manual classes had a substantial unexplained risk of disability pension. Work-related factors only had a moderate impact on the disability risk. Literature indicates an accumulation of hazards in the

Global regulation of post-translational modifications on core histones.

PubMed

Galasinski, Scott C; Louie, Donna F; Gloor, Kristen K; Resing, Katheryn A; Ahn, Natalie G

2002-01-25

Full-length masses of histones were analyzed by mass spectrometry to characterize post-translational modifications of bulk histones and their changes induced by cell stimulation. By matching masses of unique peptides with full-length masses, H4 and the variants H2A.1, H2B.1, and H3.1 were identified as the main histone forms in K562 cells. Mass changes caused by covalent modifications were measured in a dose- and time-dependent manner following inhibition of phosphatases by okadaic acid. Histones H2A, H3, and H4 underwent changes in mass consistent with altered acetylation and phosphorylation, whereas H2B mass was largely unchanged. Unexpectedly, histone H4 became almost completely deacetylated in a dose-dependent manner that occurred independently of phosphorylation. Okadaic acid also partially blocked H4 hyperacetylation induced by trichostatin-A, suggesting that the mechanism of deacetylation involves inhibition of H4 acetyltransferase activity, following perturbation of cellular phosphatases. In addition, mass changes in H3 in response to okadaic acid were consistent with phosphorylation of methylated, acetylated, and phosphorylated forms. Finally, kinetic differences were observed with respect to the rate of phosphorylation of H2A versus H4, suggesting differential regulation of phosphorylation at sites on these proteins, which are highly related by sequence. These results provide novel evidence that global covalent modifications of chromatin-bound histones are regulated through phosphorylation-dependent mechanisms.

Occupational gender composition and mild to severe depression in a Swedish cohort: The impact of psychosocial work factors.

PubMed

Nyberg, Anna; Magnusson Hanson, Linda L; Leineweber, Constanze; Hammarström, Anne; Theorell, Töres

2018-05-01

The aim of the present study was to investigate associations between occupational gender composition, psychosocial work factors and mild to severe depression in Swedish women and men with various educational backgrounds. The study included 5560 participants from two waves of the Swedish Longitudinal Occupational Survey of Health, an approximately representative sample of the Swedish working population. Odds ratios (OR) and 95% confidence intervals of mild to severe depression in 2014 were estimated for five strata of occupational gender composition with >20-40%, >40-60%, >60-80% and >80-100% women, using 0-20% women as the reference. Analyses were stratified by gender and education. Job strain, organisational injustice, poor social support and effort-reward imbalance in 2012 were added in separate models, and changes in OR of mild to severe depression for strata of occupational gender composition were evaluated. Among women, the odds of mild to severe depression did not vary by occupational gender composition. Among men with low to intermediate education, the odds were higher in the stratum with >80-100% women, and among men with high education, the odds were higher in strata with >20-40% and >60-80% women. Psychosocial work factors affected the odds ratios of mild to severe depression, but most of the variation remained unexplained. Odds of mild to severe depression appeared to vary by occupational gender composition among Swedish men but not women. This variation seemed only to a small extent to be explained by psychosocial work factors.

CSR-1 RNAi pathway positively regulates histone expression in C. elegans

PubMed Central

Avgousti, Daphne C; Palani, Santhosh; Sherman, Yekaterina; Grishok, Alla

2012-01-01

Endogenous small interfering RNAs (endo-siRNAs) have been discovered in many organisms, including mammals. In C. elegans, depletion of germline-enriched endo-siRNAs found in complex with the CSR-1 Argonaute protein causes sterility and defects in chromosome segregation in early embryos. We discovered that knockdown of either csr-1, the RNA-dependent RNA polymerase (RdRP) ego-1, or the dicer-related helicase drh-3, leads to defects in histone mRNA processing, resulting in severe depletion of core histone proteins. The maturation of replication-dependent histone mRNAs, unlike that of other mRNAs, requires processing of their 3′UTRs through an endonucleolytic cleavage guided by the U7 snRNA, which is lacking in C. elegans. We found that CSR-1-bound antisense endo-siRNAs match histone mRNAs and mRNA precursors. Consistently, we demonstrate that CSR-1 directly binds to histone mRNA in an ego-1-dependent manner using biotinylated 2′-O-methyl RNA oligonucleotides. Moreover, we demonstrate that increasing the dosage of histone genes rescues the lethality associated with depletion of CSR-1 and EGO-1. These results support a positive and direct effect of RNAi on histone gene expression. PMID:22863779

CSR-1 RNAi pathway positively regulates histone expression in C. elegans.

PubMed

Avgousti, Daphne C; Palani, Santhosh; Sherman, Yekaterina; Grishok, Alla

2012-10-03

Endogenous small interfering RNAs (endo-siRNAs) have been discovered in many organisms, including mammals. In C. elegans, depletion of germline-enriched endo-siRNAs found in complex with the CSR-1 Argonaute protein causes sterility and defects in chromosome segregation in early embryos. We discovered that knockdown of either csr-1, the RNA-dependent RNA polymerase (RdRP) ego-1, or the dicer-related helicase drh-3, leads to defects in histone mRNA processing, resulting in severe depletion of core histone proteins. The maturation of replication-dependent histone mRNAs, unlike that of other mRNAs, requires processing of their 3'UTRs through an endonucleolytic cleavage guided by the U7 snRNA, which is lacking in C. elegans. We found that CSR-1-bound antisense endo-siRNAs match histone mRNAs and mRNA precursors. Consistently, we demonstrate that CSR-1 directly binds to histone mRNA in an ego-1-dependent manner using biotinylated 2'-O-methyl RNA oligonucleotides. Moreover, we demonstrate that increasing the dosage of histone genes rescues the lethality associated with depletion of CSR-1 and EGO-1. These results support a positive and direct effect of RNAi on histone gene expression.

Linker histone partial phosphorylation: effects on secondary structure and chromatin condensation

PubMed Central

Lopez, Rita; Sarg, Bettina; Lindner, Herbert; Bartolomé, Salvador; Ponte, Inma; Suau, Pedro; Roque, Alicia

2015-01-01

Linker histones are involved in chromatin higher-order structure and gene regulation. We have successfully achieved partial phosphorylation of linker histones in chicken erythrocyte soluble chromatin with CDK2, as indicated by HPCE, MALDI-TOF and Tandem MS. We have studied the effects of linker histone partial phosphorylation on secondary structure and chromatin condensation. Infrared spectroscopy analysis showed a gradual increase of β-structure in the phosphorylated samples, concomitant to a decrease in α-helix/turns, with increasing linker histone phosphorylation. This conformational change could act as the first step in the phosphorylation-induced effects on chromatin condensation. A decrease of the sedimentation rate through sucrose gradients of the phosphorylated samples was observed, indicating a global relaxation of the 30-nm fiber following linker histone phosphorylation. Analysis of specific genes, combining nuclease digestion and qPCR, showed that phosphorylated samples were more accessible than unphosphorylated samples, suggesting local chromatin relaxation. Chromatin aggregation was induced by MgCl2 and analyzed by dynamic light scattering (DLS). Phosphorylated chromatin had lower percentages in volume of aggregated molecules and the aggregates had smaller hydrodynamic diameter than unphosphorylated chromatin, indicating that linker histone phosphorylation impaired chromatin aggregation. These findings provide new insights into the effects of linker histone phosphorylation in chromatin condensation. PMID:25870416

Nucleosome Recognition by the Piccolo NuA4 Histone Acetyltransferase Complex†

PubMed Central

Berndsen, Christopher E.; Selleck, William; McBryant, Steven J.; Hansen, Jeffrey C.; Tan, Song; Demi, John M.

2007-01-01

The mechanisms by which multisubunit histone acetyltransferase (HAT) complexes recognize and perform efficient acetylation on nucleosome substrates are largely unknown. Here, we use a variety of biochemical approaches and compare histone-based substrates of increasing complexity to determine the critical components of nucleosome recognition by the MOZ, Ybf2/Sas3, Sas2, Tip60 family HAT complex, Piccolo NuA4 (picNuA4). We find the histone tails to be dispensable for binding to both nucleosomes and free histones and that the H2A, H3, and H2B tails do not influence the ability of picNuA4 to tetra-acetylate the H4 tail within the nucleosome. Most notably, we discovered that the histone-fold domain (HFD) regions of histones, particularly residues 21–52 of H4, are critical for tight binding and efficient tail acetylation. Presented evidence suggests that picNuA4 recognizes the open surface of the nucleosome on which the HFD of H4 is located. This binding mechanism serves to direct substrate access to the tails of H4 and H2A and allows the enzyme to be “tethered”, thereby increasing the effective concentration of the histone tail and permitting successive cycles of H4 tail acetylation. PMID:17274630

NOK mediates glycolysis and nuclear PDC associated histone acetylation.

PubMed

Shi, Wei-Ye; Yang, Xiao; Huang, Bo; Shen, Wen H; Liu, Li

2017-06-01

NOK is a potent oncogene that can transform normal cells to cancer cells. We hypothesized that NOK might impact cancer cell metabolism and histone acetylation. We show that NOK localizes in the mitochondria, and while it minimally impacts tricarboxylic acid (TCA) cycle, it markedly inhibits the process of electron transport and oxidative phosphorylation processes and dramatically enhances aerobic glycolysis in cancer cells. NOK promotes the mitochondrial-nuclear translocation of pyruvate dehydrogenase complex (PDC), and enhances histone acetylation in the nucleus. Together, these findings show that NOK mediates glycolysis and nuclear PDC associated histone acetylation.

Identification and Characterization of Switchgrass Histone H3 and CENH3 Genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miao, Jiamin; Frazier, Taylor; Huang, Linkai

Switchgrass is one of the most promising energy crops and only recently has been employed for biofuel production. The draft genome of switchgrass was recently released; however, relatively few switchgrass genes have been functionally characterized. CENH3, the major histone protein found in centromeres, along with canonical H3 and other histones, plays an important role in maintaining genome stability and integrity. Despite their importance, the histone H3 genes of switchgrass have remained largely uninvestigated. In this study, we identified 17 putative switchgrass histone H3 genes in silico. Of these genes, 15 showed strong homology to histone H3 genes including six H3.1more » genes, three H3.3 genes, four H3.3-like genes and two H3.1-like genes. The remaining two genes were found to be homologous to CENH3. RNA-seq data derived from lowland cultivar Alamo and upland cultivar Dacotah allowed us to identify SNPs in the histone H3 genes and compare their differential gene expression. Interestingly, we also found that overexpression of switchgrass histone H3 and CENH3 genes in N. benthamiana could trigger cell death of the transformed plant cells. Localization and deletion analyses of the histone H3 and CENH3 genes revealed that nuclear localization of the N-terminal tail is essential and sufficient for triggering the cell death phenotype. Lastly, our results deliver insight into the mechanisms underlying the histone-triggered cell death phenotype and provide a foundation for further studying the variations of the histone H3 and CENH3 genes in switchgrass.« less

Identification and Characterization of Switchgrass Histone H3 and CENH3 Genes

DOE PAGES

Miao, Jiamin; Frazier, Taylor; Huang, Linkai; ...

2016-07-12

Switchgrass is one of the most promising energy crops and only recently has been employed for biofuel production. The draft genome of switchgrass was recently released; however, relatively few switchgrass genes have been functionally characterized. CENH3, the major histone protein found in centromeres, along with canonical H3 and other histones, plays an important role in maintaining genome stability and integrity. Despite their importance, the histone H3 genes of switchgrass have remained largely uninvestigated. In this study, we identified 17 putative switchgrass histone H3 genes in silico. Of these genes, 15 showed strong homology to histone H3 genes including six H3.1more » genes, three H3.3 genes, four H3.3-like genes and two H3.1-like genes. The remaining two genes were found to be homologous to CENH3. RNA-seq data derived from lowland cultivar Alamo and upland cultivar Dacotah allowed us to identify SNPs in the histone H3 genes and compare their differential gene expression. Interestingly, we also found that overexpression of switchgrass histone H3 and CENH3 genes in N. benthamiana could trigger cell death of the transformed plant cells. Localization and deletion analyses of the histone H3 and CENH3 genes revealed that nuclear localization of the N-terminal tail is essential and sufficient for triggering the cell death phenotype. Lastly, our results deliver insight into the mechanisms underlying the histone-triggered cell death phenotype and provide a foundation for further studying the variations of the histone H3 and CENH3 genes in switchgrass.« less

Absolute quantification of histone PTM marks by MRM-based LC-MS/MS.

PubMed

Gao, Jun; Liao, Rijing; Yu, Yanyan; Zhai, Huili; Wang, Yingqi; Sack, Ragna; Peters, Antoine H F M; Chen, Jiajia; Wu, Haiping; Huang, Zheng; Hu, Min; Qi, Wei; Lu, Chris; Atadja, Peter; Oyang, Counde; Li, En; Yi, Wei; Zhou, Shaolian

2014-10-07

The N-terminal tails of core histones harbor the sites of numerous post-translational modifications (PTMs) with important roles in the regulation of chromatin structure and function. Profiling histone PTM marks provides data that help understand the epigenetics events in cells and their connections with cancer and other diseases. Our previous study demonstrated that specific derivatization of histone peptides by NHS propionate significantly improved their chromatographic performance on reversed phase columns for LC/MS analysis. As a step forward, we recently developed a multiple reaction monitoring (MRM) based LC-MS/MS method to analyze 42 targeted histone peptides. By using stable isotopic labeled peptides as internal standards that are spiked into the reconstituted solutions, this method allows to measure absolute concentration of the tryptic peptides of H3 histone proteins extracted from cancer cell lines. The method was thoroughly validated for the accuracy and reproducibility through analyzing recombinant histone proteins and cellular samples. The linear dynamic range of the MRM assays was achieved in 3 orders of magnitude from 1 nM to 1 μM for all targeted peptides. Excellent intrabatch and interbatch reproducibility (<15% CV) was obtained. This method has been used to study translocated NSD2 (a histone lysine methyltransferase that catalyzes the histone lysine 36 methylation) function with its overexpression in KMS11 multiple myeloma cells. From the results we have successfully quantitated both individual and combinatorial histone marks in parental and NSD2 selective knockout KMS11 cells.

Histone Methylation Restrains the Expression of Subtype-Specific Genes during Terminal Neuronal Differentiation in Caenorhabditis elegans

PubMed Central

Chiang, Victor; Chalfie, Martin

2013-01-01

Although epigenetic control of stem cell fate choice is well established, little is known about epigenetic regulation of terminal neuronal differentiation. We found that some differences among the subtypes of Caenorhabditis elegans VC neurons, particularly the expression of the transcription factor gene unc-4, require histone modification, most likely H3K9 methylation. An EGF signal from the vulva alleviated the epigenetic repression of unc-4 in vulval VC neurons but not the more distant nonvulval VC cells, which kept unc-4 silenced. Loss of the H3K9 methyltransferase MET-2 or H3K9me2/3 binding proteins HPL-2 and LIN-61 or a novel chromodomain protein CEC-3 caused ectopic unc-4 expression in all VC neurons. Downstream of the EGF signaling in vulval VC neurons, the transcription factor LIN-11 and histone demethylases removed the suppressive histone marks and derepressed unc-4. Behaviorally, expression of UNC-4 in all the VC neurons caused an imbalance in the egg-laying circuit. Thus, epigenetic mechanisms help establish subtype-specific gene expression, which are needed for optimal activity of a neural circuit. PMID:24348272

Histone H3 Lysine 36 Methyltransferase Whsc1 Promotes the Association of Runx2 and p300 in the Activation of Bone-Related Genes

PubMed Central

Lee, Yu Fei; Nimura, Keisuke; Lo, Wan Ning; Saga, Kotaro; Kaneda, Yasufumi

2014-01-01

The orchestration of histone modifiers is required to establish the epigenomic status that regulates gene expression during development. Whsc1 (Wolf-Hirschhorn Syndrome candidate 1), a histone H3 lysine 36 (H3K36) trimethyltransferase, is one of the major genes associated with Wolf-Hirshhorn syndrome, which is characterized by skeletal abnormalities. However, the role of Whsc1 in skeletal development remains unclear. Here, we show that Whsc1 regulates gene expression through Runt-related transcription factor (Runx) 2, a transcription factor central to bone development, and p300, a histone acetyltransferase, to promote bone differentiation. Whsc1 −/− embryos exhibited defects in ossification in the occipital bone and sternum. Whsc1 knockdown in pre-osteoblast cells perturbed histone modification patterns in bone-related genes and led to defects in bone differentiation. Whsc1 increased the association of p300 with Runx2, activating the bone-related genes Osteopontin (Opn) and Collagen type Ia (Col1a1), and Whsc1 suppressed the overactivation of these genes via H3K36 trimethylation. Our results suggest that Whsc1 fine-tunes the expression of bone-related genes by acting as a modulator in balancing H3K36 trimethylation and histone acetylation. Our results provide novel insight into the mechanisms by which this histone methyltransferase regulates gene expression. PMID:25188294

Histone deacetylase inhibitors augment doxorubicin-induced DNA damage in cardiomyocytes.

PubMed

Ververis, Katherine; Rodd, Annabelle L; Tang, Michelle M; El-Osta, Assam; Karagiannis, Tom C

2011-12-01

Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutics with suberoylanilide hydroxamic acid (Vorinostat) and depsipeptide (Romidepsin) already being approved for clinical use. Numerous studies have identified that histone deacetylase inhibitors will be most effective in the clinic when used in combination with conventional cancer therapies such as ionizing radiation and chemotherapeutic agents. One promising combination, particularly for hematologic malignancies, involves the use of histone deacetylase inhibitors with the anthracycline, doxorubicin. However, we previously identified that trichostatin A can potentiate doxorubicin-induced hypertrophy, the dose-limiting side-effect of the anthracycline, in cardiac myocytes. Here we have the extended the earlier studies and evaluated the effects of combinations of the histone deacetylase inhibitors, trichostatin A, valproic acid and sodium butyrate on doxorubicin-induced DNA double-strand breaks in cardiomyocytes. Using γH2AX as a molecular marker for the DNA lesions, we identified that all of the broad-spectrum histone deacetylase inhibitors tested augment doxorubicin-induced DNA damage. Furthermore, it is evident from the fluorescence photomicrographs of stained nuclei that the histone deacetylase inhibitors also augment doxorubicin-induced hypertrophy. These observations highlight the importance of investigating potential side-effects, in relevant model systems, which may be associated with emerging combination therapies for cancer.

The linkage between patterns of daily occupations and occupational balance: Applications within occupational science and occupational therapy practice.

PubMed

Eklund, Mona; Orban, Kristina; Argentzell, Elisabeth; Bejerholm, Ulrika; Tjörnstrand, Carina; Erlandsson, Lena-Karin; Håkansson, Carita

2017-01-01

Patterns of daily occupations (PDO) and occupational balance (OB) are recurring phenomena in the literature. Both are related with health and well-being, which makes them central in occupational therapy practice and occupational science. The aim was to review how PDO and OB are described in the literature, to propose a view of how the two constructs may be linked, and elaborate on how such a view may benefit occupational science and occupational therapy. The literature was analysed by latent and manifest content analysis and comparative analysis. The findings were summarized in a model, framing PDO as the more objective and OB as the more subjective result from an interaction between personal preferences and environmental influences. The proposed model does not assume a cause-effect relationship between the targeted constructs, rather a mutual influence and a joint reaction to influencing factors. Indicators of PDO and OB were identified, as well as tools for assessing PDO and OB. The authors propose that discerning PDO and OB as separate but interacting phenomena may be useful in developing a theoretical discourse in occupational science and enhancing occupational therapy practice. Although the scope of this study was limited, the proposed view may hopefully inspire further scrutiny of constructs.

A Structural Perspective on Readout of Epigenetic Histone and DNA Methylation Marks

PubMed Central

Patel, Dinshaw J.

2016-01-01

SUMMARY This article outlines the protein modules that target methylated lysine histone marks and 5mC DNA marks, and the molecular principles underlying recognition. The article focuses on the structural basis underlying readout of isolated marks by single reader molecules, as well as multivalent readout of multiple marks by linked reader cassettes at the histone tail and nucleosome level. Additional topics addressed include the role of histone mimics, cross talk between histone marks, technological developments at the genome-wide level, advances using chemical biology approaches, the linkage between histone and DNA methylation, the role for regulatory lncRNAs, and the promise of chromatin-based therapeutic modalities. PMID:26931326

Chemical and Biological Tools for the Preparation of Modified Histone Proteins

PubMed Central

Howard, Cecil J.; Yu, Ruixuan R.; Gardner, Miranda L.; Shimko, John C.; Ottesen, Jennifer J.

2016-01-01

Eukaryotic chromatin is a complex and dynamic system in which the DNA double helix is organized and protected by interactions with histone proteins. This system is regulated through, a large network of dynamic post-translational modifications (PTMs) exists to ensure proper gene transcription, DNA repair, and other processes involving DNA. Homogenous protein samples with precisely characterized modification sites are necessary to better understand the functions of modified histone proteins. Here, we discuss sets of chemical and biological tools that have been developed for the preparation of modified histones, with a focus on the appropriate choice of tool for a given target. We start with genetic approaches for the creation of modified histones, including the incorporation of genetic mimics of histone modifications, chemical installation of modification analogs, and the use of the expanded genetic code to incorporate modified amino acids. Additionally, we will cover the chemical ligation techniques that have been invaluable in the generation of complex modified histones that are indistinguishable from the natural counterparts. Finally, we will end with a prospectus on future directions of synthetic chromatin in living systems. PMID:25863817

Post-Training Intrahippocampal Inhibition of Class I Histone Deacetylases Enhances Long-Term Object-Location Memory

ERIC Educational Resources Information Center

Hawk, Joshua D.; Florian, Cedrick; Abel, Ted

2011-01-01

Long-term memory formation involves covalent modification of the histone proteins that package DNA. Reducing histone acetylation by mutating histone acetyltransferases impairs long-term memory, and enhancing histone acetylation by inhibiting histone deacetylases (HDACs) improves long-term memory. Previous studies using HDAC inhibitors to enhance…

Chromatin signaling to kinetochores: Trans-regulation of Dam1 methylation by histone H2B ubiquitination

PubMed Central

Latham, John A.; Chosed, Renée J.; Wang, Shanzhi; Dent, Sharon Y.R.

2011-01-01

Summary Histone H3K4 trimethylation by the Set1/MLL family of proteins provides a hallmark for transcriptional activity from yeast to humans. In S. cerevisiae, H3K4 methylation is mediated by the Set1-containing COMPASS complex and is regulated in trans by prior ubiquitination of histone H2BK123. All of the events that regulate H2BK123ub and H3K4me are thought to occur at gene promoters. Here we report that this pathway is indispensable for methylation of the only other known substrate of Set1, K233 in Dam1, at kinetochores. Deletion of RAD6, BRE1, or Paf1 complex members abolishes Dam1 methylation, as does mutation of H2BK123. Our results demonstrate that Set1-mediated methylation is regulated by a general pathway regardless of substrate that is composed of transcriptional regulatory factors functioning independently of transcription. Moreover, our data identify a node of regulatory cross-talk in trans between a histone modification and modification on a non-histone protein, demonstrating that changing chromatin states can signal functional changes in other essential cellular proteins and machineries. PMID:21884933

The Cac2 subunit is essential for productive histone binding and nucleosome assembly in CAF-1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mattiroli, Francesca; Gu, Yajie; Balsbaugh, Jeremy L.

Nucleosome assembly following DNA replication controls epigenome maintenance and genome integrity. Chromatin assembly factor 1 (CAF-1) is the histone chaperone responsible for histone (H3-H4)2 deposition following DNA synthesis. Structural and functional details for this chaperone complex and its interaction with histones are slowly emerging. Using hydrogen-deuterium exchange coupled to mass spectrometry, combined with in vitro and in vivo mutagenesis studies, we identified the regions involved in the direct interaction between the yeast CAF-1 subunits, and mapped the CAF-1 domains responsible for H3-H4 binding. The large subunit, Cac1 organizes the assembly of CAF-1. Strikingly, H3-H4 binding is mediated by a compositemore » interface, shaped by Cac1-bound Cac2 and the Cac1 acidic region. Cac2 is indispensable for productive histone binding, while deletion of Cac3 has only moderate effects on H3-H4 binding and nucleosome assembly. These results define direct structural roles for yeast CAF-1 subunits and uncover a previously unknown critical function of the middle subunit in CAF-1.« less

The C Terminus of the Histone Chaperone Asf1 Cross-Links to Histone H3 in Yeast and Promotes Interaction with Histones H3 and H4

PubMed Central

Dennehey, Briana K.; Noone, Seth; Liu, Wallace H.; Smith, Luke

2013-01-01

The central histone H3/H4 chaperone Asf1 comprises a highly conserved globular core and a divergent C-terminal tail. While the function and structure of the Asf1 core are well known, the function of the tail is less well understood. Here, we have explored the role of the yeast (yAsf1) and human (hAsf1a and hAsf1b) Asf1 tails in Saccharomyces cerevisiae. We show, using a photoreactive, unnatural amino acid, that Asf1 tail residue 210 cross-links to histone H3 in vivo and, further, that loss of C-terminal tail residues 211 to 279 weakens yAsf1-histone binding affinity in vitro nearly 200-fold. Via several yAsf1 C-terminal truncations and yeast-human chimeric proteins, we found that truncations at residue 210 increase transcriptional silencing and that the hAsf1a tail partially substitutes for full-length yAsf1 with respect to silencing but that full-length hAsf1b is a better overall substitute for full-length yAsf1. In addition, we show that the C-terminal tail of Asf1 is phosphorylated at T270 in yeast. Loss of this phosphorylation site does not prevent coimmunoprecipitation of yAsf1 and Rad53 from yeast extracts, whereas amino acid residue substitutions at the Asf1-histone H3/H4 interface do. Finally, we show that residue substitutions in yAsf1 near the CAF-1/HIRA interface also influence yAsf1's function in silencing. PMID:23184661

Interplay between DNA methylation, histone modification and chromatin remodeling in stem cells and during development.

PubMed

Ikegami, Kohta; Ohgane, Jun; Tanaka, Satoshi; Yagi, Shintaro; Shiota, Kunio

2009-01-01

Genes constitute only a small proportion of the mammalian genome, the majority of which is composed of non-genic repetitive elements including interspersed repeats and satellites. A unique feature of the mammalian genome is that there are numerous tissue-dependent, differentially methylated regions (T-DMRs) in the non-repetitive sequences, which include genes and their regulatory elements. The epigenetic status of T-DMRs varies from that of repetitive elements and constitutes the DNA methylation profile genome-wide. Since the DNA methylation profile is specific to each cell and tissue type, much like a fingerprint, it can be used as a means of identification. The formation of DNA methylation profiles is the basis for cell differentiation and development in mammals. The epigenetic status of each T-DMR is regulated by the interplay between DNA methyltransferases, histone modification enzymes, histone subtypes, non-histone nuclear proteins and non-coding RNAs. In this review, we will discuss how these epigenetic factors cooperate to establish cell- and tissue-specific DNA methylation profiles.

Histone retention, protein carbonylation, and lipid peroxidation in spermatozoa: Possible role in recurrent pregnancy loss.

PubMed

Mohanty, Gayatri; Swain, Nirlipta; Goswami, Chandan; Kar, Sujata; Samanta, Luna

2016-06-01

Contribution from a defective paternal genome has been attributed to be an important cause for spontaneous recurrent pregnancy loss (RPL). Increased oxidative stress results in decreased detoxification and is a cause for damage to chromatin, proteins, and membrane lipids. The present study aimed to explore if there is a significant relationship between retained histones due to defective packaging of DNA in spermatozoa and oxidative stress. RPL patients (n=16) with a history of ≥2 embryo losses before the 20th week of gestation and no female factor abnormality, and fertile healthy volunteers (n=20) as controls were included in the study. A significant difference in the levels of protein carbonylation and lipid peroxidation together with an increased retention of histones in the experimental groups was noticed. Histone carrying sites for oxidative modification such as arginine and lysine might be responsible for disturbing the paternal epigenomic control during early stages of embryonic differentiation leading to abortion.

Impact of occupational stress and other psychosocial factors on musculoskeletal pain among Chinese offshore oil installation workers

PubMed Central

Chen, W; Yu, I; Wong, T

2005-01-01

Aims: To explore the relation between psychosocial factors and musculoskeletal pain in Chinese offshore oil installation workers. Methods: Half of all offshore workers (being a representative sample) in a Chinese oil company were invited to complete a self-administered questionnaire providing information on sociodemographic characteristics, occupational stressors, type A behaviour, social support, coping style, health related behaviour, past injuries, and musculoskeletal pain. Factor analysis was used to identify the sources of occupational stress and the domains of type A behaviour and coping style. Logistic regression analyses were used to study the relations between psychosocial factors and musculoskeletal pain in each body region. Results: The prevalence of musculoskeletal pain over the previous 12 months varied between 7.5% for elbow pain and 32% for low back pain; 56% workers had at least one complaint. Significant associations were found between various psychosocial factors and musculoskeletal pain in different body regions after adjusting for potential confounding factors. Occupational stressors, in particular stress from safety, physical environment, and ergonomics, were important predictors of musculoskeletal pain, as was coping by eating behaviour. Conclusions: These observations supported the widely accepted biopsychosocial model of musculoskeletal disorders and suggested that in future studies of work related musculoskeletal disorders, psychosocial factors must be given due consideration. PMID:15778258

Interaction of Physical Exposures and Occupational Factors on Sickness Absence in Automotive Industry Workers.

PubMed

Valirad, Fateme; Ghaffari, Mostafa; Abdi, Alireza; Attarchi, Mirsaeed; Mircheraghi, Seyed Farzin; Mohammadi, Saber

2015-04-23

Increased sickness absence in recent years has been a trouble making issue in industrial society. Identify the causes of sickness absence and its influencing factors, is an important step to control and reduce its associated complications and costs. The aim of this study was to evaluate main factors associated with the incidence of sickness absence. In 2012, a cross-sectional study on 758 employees of a car accessories producing company was applied and relevant information about the number of days and episodes of sickness absence, Disease resulting in absence from work, personal features, occupational factors and physical exposures were collected. To determine risk factors associated with sickness absence, Logistic regression analysis was used. The most common diseases leading to sickness absence in order of frequency were Respiratory diseases, musculoskeletal disorders, gastrointestinal diseases and injuries at work. Musculoskeletal disorders increased the danger of long term absence by 4/33 times. Blue collar and shift works were the most important occupational factors associated with the incidence of sickness absence. The main physical factors that affect incidence of sickness absence were frequent bending-twisting and heavy lifting. Identifying controllable factors of sickness absence and trying to prevent and modify them such as compliance of ergonomic principals to decrease physical can be effective in reducing sickness absence.

Anti-Inflammatory Effects of Spirulina platensis Extract via the Modulation of Histone Deacetylases.

PubMed

Pham, Tho X; Park, Young-Ki; Lee, Ji-Young

2016-06-21

We previously demonstrated that the organic extract of Spirulina platensis (SPE), an edible blue-green alga, possesses potent anti-inflammatory effects. In this study, we investigated if the regulation of histone deacetylases (HDACs) play a role in the anti-inflammatory effect of SPE in macrophages. Treatment of macrophages with SPE rapidly and dose-dependently reduced HDAC2, 3, and 4 proteins which preceded decreases in their mRNA levels. Degradation of HDAC4 protein was attenuated in the presence of inhibitors of calpain proteases, lysosomal acidification, and Ca(2+)/calmodulin-dependent protein kinase II, respectively, but not a proteasome inhibitor. Acetylated histone H3 was increased in SPE-treated macrophages to a similar level as macrophages treated with a pan-HDAC inhibitor, with concomitant inhibition of inflammatory gene expression upon LPS stimulation. Knockdown of HDAC3 increased basal and LPS-induced pro-inflammatory gene expression, while HDAC4 knockdown increased basal expression of interleukin-1β (IL-1β), but attenuated LPS-induced inflammatory gene expression. Chromatin immunoprecipitation showed that SPE decreased p65 binding and H3K9/K14 acetylation at the Il-1β and tumor necrosis factor α (Tnfα) promoters. Our results suggest that SPE increased global histone H3 acetylation by facilitating HDAC protein degradation, but decreases histone H3K9/K14 acetylation and p65 binding at the promoters of Il-1β and Tnfα to exert its anti-inflammatory effect.

Chemical and Biochemical Approaches in the Study of Histone Methylation and Demethylation

PubMed Central

Li, Keqin Kathy; Luo, Cheng; Wang, Dongxia; Jiang, Hualiang; Zheng, Y. George

2014-01-01

Histone methylation represents one of the most critical epigenetic events in DNA function regulation in eukaryotic organisms. Classic molecular biology and genetics tools provide significant knowledge about mechanisms and physiological roles of histone methyltransferases and demethylases in various cellular processes. In addition to this stream line, development and application of chemistry and chemistry-related techniques are increasingly involved in biological study, and provide information otherwise difficulty to obtain by standard molecular biology methods. Herein, we review recent achievements and progress in developing and applying chemical and biochemical approaches in the study of histone methylation, including chromatin immunoprecipitation (ChIP), chemical ligation, mass spectrometry (MS), biochemical assays, and inhibitor development. These technological advances allow histone methylation to be studied from genome-wide level to molecular and atomic levels. With ChIP technology, information can be obtained about precise mapping of histone methylation patterns at specific promoters, genes or other genomic regions. MS is particularly useful in detecting and analyzing methylation marks in histone and nonhistone protein substrates. Chemical approaches that permit site-specific incorporation of methyl groups into histone proteins greatly facilitate the investigation of the biological impacts of methylation at individual modification sites. Discovery and design of selective organic inhibitors of histone methyltransferases and demethylases provide chemical probes to interrogate methylation-mediated cellular pathways. Overall, these chemistry-related technological advances have greatly improved our understanding of the biological functions of histone methylation in normal physiology and diseased states, and also are of great potential to translate basic epigenetics research into diagnostic and therapeutic application in the clinic. PMID:22777714

Unliganded Thyroid Hormone Receptor Regulates Metamorphic Timing via the Recruitment of Histone Deacetylase Complexes

PubMed Central

2014-01-01

Anuran metamorphosis involves a complex series of tissue transformations that change an aquatic tadpole to a terrestrial frog and resembles the postembryonic perinatal period in mammals. Thyroid hormone (TH) plays a causative role in amphibian metamorphosis and its effect is mediated by TH receptors (TRs). Molecular analyses during Xenopus development have shown that unliganded TR recruits histone deacetylase (HDAC)-containing N-CoR/SMRT complexes and causes histone deacetylation at target genes while liganded TR leads to increased histone acetylations and altered histone methylations at target genes. Transgenic studies involving mutant TR-cofactors have shown that corepressor recruitment by unliganded TR is required to ensure proper timing of the onset of metamorphosis while coactivator levels influence the rate of metamorphic progression. In addition, a number of factors that can influence cellular free TH levels appear to contribute the timing of metamorphic transformations of different organs by regulating the levels of unliganded vs. liganded TR in an organ-specific manner. Thus, the recruitment of HDAC-containing corepressor complexes by unliganded TR likely controls both the timing of the initiation of metamorphosis and the temporal regulation of organ-specific transformations. Similar mechanisms likely mediate TR function in mammals as the maturation of many organs during postembryonic development is dependent upon TH and resembles organ metamorphosis in amphibians. PMID:23962846

Occupational and environmental risk factors of the myelodysplastic syndromes in the North of France.

PubMed

Nisse, C; Haguenoer, J M; Grandbastien, B; Preudhomme, C; Fontaine, B; Brillet, J M; Lejeune, R; Fenaux, P

2001-03-01

Aetiological factors of the myelodysplastic syndromes (MDS) are largely unknown, with the exception of alkylating agents, ionizing radiation and benzene. Some other risk factors have been suggested by the few epidemiological studies reported (solvents, ammonia, exhaust gases, metals, pesticides, alcohol). We performed a case-control study to assess the relationship between occupational or environmental factors and MDS. Two hundred and four patients with newly diagnosed MDS, and 204 sex- and age-matched controls were included. Medical history, demographic data, lifetime exposure and hobbies were obtained. Qualitative and quantitative exposure to chemical and physical hazards were evaluated with the patients and reviewed by a group of experts in occupational exposure. The median age was 70 years and 62% of the patients were men. In univariate analyses, we found relationships between MDS and smoking habits, gardening, occupations such as health professionals, technical and sale representatives, machine operators, agricultural workers, textile workers, qualitative occupational exposures (exposed/non-exposed) to oil, solvents, ammonia, pesticides, fertilizers, cereal dusts, contact with poultry or livestock and infective risk, and lifetime cumulative exposure to solvents, oil, textile dust and infective risk. The main risk factors of MDS determined by multivariate analyses (conditional logistic regression) were, being an agricultural worker [odds ratio (OR) = 3.66; 95% confidence interval (CI) 1.9-7.0], textile operator (OR = 3.66; 95% CI 1.9-7.9), health professional (OR = 10.0; 95% CI 2.1-48.7), commercial and technical sale representative (OR = 4.45; 95% CI 1.4-14.6), machine operator (OR = 2.69; 95% CI 1.2-6.0), living next to an industrial plant (OR = 2.45; 95% CI 1.5-4.1), smoking (OR = 1.74; 95% CI 1.1-2.7) and lifetime cumulative exposure to oil (OR = 1.1; 95% CI 1.0-1.2). Further studies should be performed to assess specific exposures more precisely and it

The Histone Demethylase Jhdm1a Regulates Hepatic Gluconeogenesis

PubMed Central

Zou, Tie; Yao, Annie Y.; Cooper, Marcus P.; Boyartchuk, Victor; Wang, Yong-Xu

2012-01-01

Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36) demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPα. This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes. PMID:22719268

Prostate Cancer Prevention by Sulforaphane, a Novel Dietary Histone Deacetylase Inhibitor

DTIC Science & Technology

2008-01-01

sulforaphane , a novel dietary histone deacetylase inhibitor PRINCIPAL INVESTIGATOR: Yu Zhen CONTRACTING ORGANIZATION: Oregon State...ANNUAL 3. DATES COVERED 1 JAN 2007 - 31 DEC 2007 4. TITLE AND SUBTITLE Prostate cancer prevention by sulforaphane , a novel dietary histone deacetylase...Prostate cancer is the second leading cause of cancer related death in men. To test Sulforaphane (SFN) as a novel histone deacetylases (HDAC) inhibitor

What Factors Are Associated With Occupational Health Office Staffing, Job Stress, and Job Satisfaction?

PubMed

Moses, X J Ethan; Walters, Kevin M; Fisher, Gwenith G

2016-06-01

This study sought to identify factors associated with occupational health staffing in health care settings, provide benchmarking data, and investigate relationships between staffing and worker stress and satisfaction. Members of the Association of Occupational Health Professionals in Healthcare were sent an online survey. Data on facility served, staffing, job attitudes, and work stress were collected and analyzed. Number and types of personnel served were the largest predictors of staffing, accounting for 38 and 41% of the variability seen, respectively. Number of personnel served was related to worker stress and lack of work/life balance. Offices that required a provider presence had roughly one provider, seven nurses, and three clerical staff per 8000 personnel served. Occupational health workers are generally highly satisfied, and staffing has little relation to sources of job stress and satisfaction.

Butyrate induced IGF2 activation correlated with distinct chromatin landscapes due to histone modification

USDA-ARS?s Scientific Manuscript database

Histone modification has emerged as a very important mechanism regulating the transcriptional status of the genome. Insulin-like growth factor 2 (IGF2) is a peptide hormone controlling various cellular processes such as proliferation and apoptosis. IGF2 and H19 are reciprocally regulated imprinted ...

Psychometric properties and factor structure of the 13-item satisfaction with daily occupations scale when used with people with mental health problems.

PubMed

Eklund, Mona; Bäckström, Martin; Eakman, Aaron M

2014-12-24

In mental health care practice and research it is increasingly recognized that clients' subjective perceptions of everyday occupations, such as satisfaction, are important in recovery from mental illness. Instruments thus need to be developed to assess satisfaction with everyday occupations. The aim of the present study was to assess psychometric properties of the 13-item Satisfaction with Daily Occupation (SDO-13) when used with people with mental health problems, including its internal consistency, factor structure, construct validity and whether the scale produced ceiling or floor effects. An additional question concerned if the factor structure varied whether the participants were, or were not, presently engaged in the activity they rated. The interview-based SDO-13 includes items pertaining to work/studies, leisure, home maintenance, and self-care occupations. Whether the person currently performs an occupation or not, he/she is asked to indicate his/her satisfaction with that occupation. The SDO-13 was completed with 184 persons with mental illness. Residual variables were created to remove the variation linked with currently performing the targeted occupation or not and to assess the factor structure of the SDO-13. The indicators of general satisfaction with daily occupations, self-esteem and global functioning were used to assess construct validity. The statistical methods included tests of homogeneity, confirmatory factor analysis and Pearson correlations. The internal consistency was satisfactory at 0.79. A three-factor solution indicated that the construct behind the SDO-13 was composed of three facets; Taking care of oneself and the home, Work and studies, and Leisure and relaxation. The same factor structure was valid for both original scores and the residuals. An expected pattern of correlations with the indicators was mainly found, suggesting basic construct validity. No ceiling or floor effects were found. Taken together, the findings suggest the

Histone H3 Variants in Trichomonas vaginalis

PubMed Central

Zubáčová, Zuzana; Hostomská, Jitka

2012-01-01

The parabasalid protist Trichomonas vaginalis is a widespread parasite that affects humans, frequently causing vaginitis in infected women. Trichomonad mitosis is marked by the persistence of the nuclear membrane and the presence of an asymmetric extranuclear spindle with no obvious direct connection to the chromosomes. No centromeric markers have been described in T. vaginalis, which has prevented a detailed analysis of mitotic events in this organism. In other eukaryotes, nucleosomes of centromeric chromatin contain the histone H3 variant CenH3. The principal aim of this work was to identify a CenH3 homolog in T. vaginalis. We performed a screen of the T. vaginalis genome to retrieve sequences of canonical and variant H3 histones. Three variant histone H3 proteins were identified, and the subcellular localization of their epitope-tagged variants was determined. The localization of the variant TVAG_185390 could not be distinguished from that of the canonical H3 histone. The sequence of the variant TVAG_087830 closely resembled that of histone H3. The tagged protein colocalized with sites of active transcription, indicating that the variant TVAG_087830 represented H3.3 in T. vaginalis. The third H3 variant (TVAG_224460) was localized to 6 or 12 distinct spots at the periphery of the nucleus, corresponding to the number of chromosomes in G1 phase and G2 phase, respectively. We propose that this variant represents the centromeric marker CenH3 and thus can be employed as a tool to study mitosis in T. vaginalis. Furthermore, we suggest that the peripheral distribution of CenH3 within the nucleus results from the association of centromeres with the nuclear envelope throughout the cell cycle. PMID:22408228

Factors influencing territorial occupancy and reproductive success in a Eurasian Eagle-owl (Bubo bubo) population.

PubMed

León-Ortega, Mario; Jiménez-Franco, María V; Martínez, José E; Calvo, José F

2017-01-01

Modelling territorial occupancy and reproductive success is a key issue for better understanding the population dynamics of territorial species. This study aimed to investigate these ecological processes in a Eurasian Eagle-owl (Bubo bubo) population in south-eastern Spain during a seven-year period. A multi-season, multi-state modelling approach was followed to estimate the probabilities of occupancy and reproductive success in relation to previous state, time and habitat covariates, and accounting for imperfect detection. The best estimated models showed past breeding success in the territories to be the most important factor determining a high probability of reoccupation and reproductive success in the following year. In addition, alternative occupancy models suggested the positive influence of crops on the probability of territory occupation. By contrast, the best reproductive model revealed strong interannual variations in the rates of breeding success, which may be related to changes in the abundance of the European Rabbit, the main prey of the Eurasian Eagle-owl. Our models also estimated the probabilities of detecting the presence of owls in a given territory and the probability of detecting evidence of successful reproduction. Estimated detection probabilities were high throughout the breeding season, decreasing in time for unsuccessful breeders but increasing for successful breeders. The probability of detecting reproductive success increased with time, being close to one in the last survey. These results suggest that reproduction failure in the early stages of the breeding season is a determinant factor in the probability of detecting occupancy and reproductive success.

Factors influencing territorial occupancy and reproductive success in a Eurasian Eagle-owl (Bubo bubo) population

PubMed Central

León-Ortega, Mario; Jiménez-Franco, María V.; Martínez, José E.

2017-01-01

Modelling territorial occupancy and reproductive success is a key issue for better understanding the population dynamics of territorial species. This study aimed to investigate these ecological processes in a Eurasian Eagle-owl (Bubo bubo) population in south-eastern Spain during a seven-year period. A multi-season, multi-state modelling approach was followed to estimate the probabilities of occupancy and reproductive success in relation to previous state, time and habitat covariates, and accounting for imperfect detection. The best estimated models showed past breeding success in the territories to be the most important factor determining a high probability of reoccupation and reproductive success in the following year. In addition, alternative occupancy models suggested the positive influence of crops on the probability of territory occupation. By contrast, the best reproductive model revealed strong interannual variations in the rates of breeding success, which may be related to changes in the abundance of the European Rabbit, the main prey of the Eurasian Eagle-owl. Our models also estimated the probabilities of detecting the presence of owls in a given territory and the probability of detecting evidence of successful reproduction. Estimated detection probabilities were high throughout the breeding season, decreasing in time for unsuccessful breeders but increasing for successful breeders. The probability of detecting reproductive success increased with time, being close to one in the last survey. These results suggest that reproduction failure in the early stages of the breeding season is a determinant factor in the probability of detecting occupancy and reproductive success. PMID:28399175

Histone 2A stimulates glucose-6-phosphatase activity by permeabilization of liver microsomes.

PubMed

Benedetti, Angelo; Fulceri, Rosella; Allan, Bernard B; Houston, Pamela; Sukhodub, Andrey L; Marcolongo, Paola; Ethell, Brian; Burchell, Brian; Burchell, Ann

2002-10-15

Histone 2A increases glucose-6-phosphatase activity in liver microsomes. The effect has been attributed either to the conformational change of the enzyme, or to the permeabilization of microsomal membrane that allows the free access of substrate to the intraluminal glucose-6-phosphatase catalytic site. The aim of the present study was the critical reinvestigation of the mechanism of action of histone 2A. It has been found that the dose-effect curve of histone 2A is different from that of detergents and resembles that of the pore-forming alamethicin. Inhibitory effects of EGTA on glucose-6-phosphatase activity previously reported in histone 2A-treated microsomes have been also found in alamethicin-permeabilized vesicles. The effect of EGTA cannot therefore simply be an antagonization of the effect of histone 2A. Histone 2A stimulates the activity of another latent microsomal enzyme, UDP-glucuronosyltransferase, which has an intraluminal catalytic site. Finally, histone 2A renders microsomal vesicles permeable to non-permeant compounds. Taken together, the results demonstrate that histone 2A stimulates glucose-6-phosphatase activity by permeabilizing the microsomal membrane.

Histone 2A stimulates glucose-6-phosphatase activity by permeabilization of liver microsomes.

PubMed Central

Benedetti, Angelo; Fulceri, Rosella; Allan, Bernard B; Houston, Pamela; Sukhodub, Andrey L; Marcolongo, Paola; Ethell, Brian; Burchell, Brian; Burchell, Ann

2002-01-01

Histone 2A increases glucose-6-phosphatase activity in liver microsomes. The effect has been attributed either to the conformational change of the enzyme, or to the permeabilization of microsomal membrane that allows the free access of substrate to the intraluminal glucose-6-phosphatase catalytic site. The aim of the present study was the critical reinvestigation of the mechanism of action of histone 2A. It has been found that the dose-effect curve of histone 2A is different from that of detergents and resembles that of the pore-forming alamethicin. Inhibitory effects of EGTA on glucose-6-phosphatase activity previously reported in histone 2A-treated microsomes have been also found in alamethicin-permeabilized vesicles. The effect of EGTA cannot therefore simply be an antagonization of the effect of histone 2A. Histone 2A stimulates the activity of another latent microsomal enzyme, UDP-glucuronosyltransferase, which has an intraluminal catalytic site. Finally, histone 2A renders microsomal vesicles permeable to non-permeant compounds. Taken together, the results demonstrate that histone 2A stimulates glucose-6-phosphatase activity by permeabilizing the microsomal membrane. PMID:12097138

Aberrant levels of histone H3 acetylation induce spermatid anomaly in mouse testis.

PubMed

Dai, Lei; Endo, Daisuke; Akiyama, Naotaro; Yamamoto-Fukuda, Tomomi; Koji, Takehiko

2015-02-01

Histone acetylation is involved in the regulation of chromatin structure and gene function. We reported previously that histone H3 acetylation pattern is subject to dynamic changes and limited to certain stages of germ cell differentiation during murine spermatogenesis, suggesting a crucial role for acetylation in the process. In the present study, we investigated the effects of hyper- and hypo-acetylation on spermatogenesis. Changes in acetylation level were induced by either in vivo administration of sodium phenylbutyrate, a histone deacetylase inhibitor, or by knockdown of histone acetyltransferases using short hairpin RNA plasmids transfection. Administration of sodium phenylbutyrate induced accumulation of acetylated histone H3 at lysine 9 and lysine 18 in round spermatids, together with spermatid morphological abnormalities and induction of apoptosis through a Bax-related pathway. Knockdown of steroid receptor coactivator 1, a member of histone acetyltransferases, but not general control of amino acid synthesis 5 nor elongator protein 3 by in vivo electroporation of shRNA plasmids, reduced acetylated histone H3 at lysine 9 in round spermatids, and induced morphological abnormalities. We concluded that the proper regulation of histone H3 acetylation levels is important for spermatid differentiation and complex chromatin remodeling during spermiogenesis.

Saturated fatty acid palmitate induces extracellular release of histone H3: A possible mechanistic basis for high-fat diet-induced inflammation and thrombosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shrestha, Chandan; Department of Laboratory and Vascular Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima; Ito, Takashi

Highlights: •High-fat diet feeding and palmitate induces the release of nuclear protein histone H3. •ROS production and JNK signaling mediates the release of histone H3. •Extracellular histones induces proinflammatory and procoagulant response. -- Abstract: Chronic low-grade inflammation is a key contributor to high-fat diet (HFD)-related diseases, such as type 2 diabetes, non-alcoholic steatohepatitis, and atherosclerosis. The inflammation is characterized by infiltration of inflammatory cells, particularly macrophages, into obese adipose tissue. However, the molecular mechanisms by which a HFD induces low-grade inflammation are poorly understood. Here, we show that histone H3, a major protein component of chromatin, is released into themore » extracellular space when mice are fed a HFD or macrophages are stimulated with the saturated fatty acid palmitate. In a murine macrophage cell line, RAW 264.7, palmitate activated reactive oxygen species (ROS) production and JNK signaling. Inhibitors of these pathways dampened palmitate-induced histone H3 release, suggesting that the extracellular release of histone H3 was mediated, in part, through ROS and JNK signaling. Extracellular histone activated endothelial cells toexpress the adhesion molecules ICAM-1 and VCAM-1 and the procoagulant molecule tissue factor, which are known to contribute to inflammatory cell recruitment and thrombosis. These results suggest the possible contribution of extracellular histone to the pathogenesis of HFD-induced inflammation and thrombosis.« less

Combination Treatments with Luteolin and Fisetin Enhance Anti-Inflammatory Effects in High Glucose-Treated THP-1 Cells Through Histone Acetyltransferase/Histone Deacetylase Regulation.

PubMed

Kim, Arang; Yun, Jung-Mi

2017-08-01

Hyperglycemia leads to diabetes and its diabetic complications. In this study, we investigated the synergistic effects of luteolin and fisetin on proinflammatory cytokine secretion and its underlying epigenetic regulation in human monocytes exposed to hyperglycemic (HG) concentrations. Human monocytic cells (THP-1) were cultured under controlled (14.5 mM mannitol), normoglycemic (5.5 mM glucose), or HG (20 mM glucose) conditions in the absence or presence of the two phytochemicals for 48 h. Whereas HG conditions significantly induced histone acetylation, nuclear factor-kappa B (NF-κB) activation, interleukin 6, and tumor necrosis factor-α release from THP-1 cells; combination treatments with the two phytochemicals (500 nM fisetin, and l μM and 500 nM luteolin) suppressed NF-κB activity and inflammatory cytokine release. Fisetin, luteolin, and their combination treatments also significantly decreased the activity of histone acetyltransferase, a known NF-κB coactivator; inhibited reactive oxygen species production; and activated sirtuin (SIRT)1 and forkhead box O3a (FOXO3a) expressions (P < .05). Thus, combination treatments with the two phytochemicals inhibited HG condition-induced cytokine production in monocytes, through epigenetic changes involving NF-κB activation. We, therefore, suggest that combination treatments with luteolin and fisetin may be a potential candidate for the treatment and prevention of diabetes and its complications.

Work and diet-related risk factors of cardiovascular diseases: comparison of two occupational groups.

PubMed

Hartung, Danielle; Stadeler, Martina; Grieshaber, Romano; Keller, Sylvia; Jahreis, Gerhard

2010-03-22

Although work related risk factors associated with Cardiovascular Diseases (CD) have been well researched, there is no detailed knowledge regarding disparate occupational groups each with a different risk exposition. Therefore, two occupational groups (chefs and office workers) were compared with a focus on nutritional and psychosocial factors. Two groups of subjects were tested for work and diet-related risks of CD (45 chefs and 48 office workers). The groups matched both for gender (male) and age (30 to 45 years). The study included a medical check-up, bioelectrical impedance analysis as well as an evaluation of questionnaires on health, nutritional behaviour and coping capacity. In addition, volunteers were required to compile a 7-day-dietary-record and collect their urine 24 h prior to their check-up. Blood samples drawn were analysed for glucose and lipid metabolism, homocysteine, vitamin B12, folic acid; C-reactive protein, uric acid, red blood cell fatty acids, plant sterols, antioxidative capacity and oxidative stress. On average, the chefs showed one risk factor more compared to the office workers. The most frequent risk factors in both groups included overweight/obesity (chef group [CG]: 62.2%; office group [OG]: 58.3%) and elevated TC (CG: 62.2%; OG: 43.8%]. Moreover, although the chefs often had higher CRP-concentrations (40.0%), more office workers suffered from hypertension (37.5%).Chefs showed significant higher concentrations of saturated fatty acids and oleic acid, whereas docosahexaenoic acid, Omega-6- and trans fatty acids were found more frequently in the red blood cell membranes of office workers. While there were no significant differences in analysed plant sterols between the two occupational groups, 7,8-dihydro-8-oxo-2'-deoxyguanosine was significantly increased in office workers.Concerning the work-related psychosocial factors, the chefs were characterised by a stronger subjective importance of work, a greater degree of professional

Work and diet-related risk factors of cardiovascular diseases: comparison of two occupational groups

PubMed Central

2010-01-01

Background Although work related risk factors associated with Cardiovascular Diseases (CD) have been well researched, there is no detailed knowledge regarding disparate occupational groups each with a different risk exposition. Therefore, two occupational groups (chefs and office workers) were compared with a focus on nutritional and psychosocial factors. Methods Two groups of subjects were tested for work and diet-related risks of CD (45 chefs and 48 office workers). The groups matched both for gender (male) and age (30 to 45 years). The study included a medical check-up, bioelectrical impedance analysis as well as an evaluation of questionnaires on health, nutritional behaviour and coping capacity. In addition, volunteers were required to compile a 7-day-dietary-record and collect their urine 24 h prior to their check-up. Blood samples drawn were analysed for glucose and lipid metabolism, homocysteine, vitamin B12, folic acid; C-reactive protein, uric acid, red blood cell fatty acids, plant sterols, antioxidative capacity and oxidative stress. Results On average, the chefs showed one risk factor more compared to the office workers. The most frequent risk factors in both groups included overweight/obesity (chef group [CG]: 62.2%; office group [OG]: 58.3%) and elevated TC (CG: 62.2%; OG: 43.8%]. Moreover, although the chefs often had higher CRP-concentrations (40.0%), more office workers suffered from hypertension (37.5%). Chefs showed significant higher concentrations of saturated fatty acids and oleic acid, whereas docosahexaenoic acid, Omega-6- and trans fatty acids were found more frequently in the red blood cell membranes of office workers. While there were no significant differences in analysed plant sterols between the two occupational groups, 7,8-dihydro-8-oxo-2'-deoxyguanosine was significantly increased in office workers. Concerning the work-related psychosocial factors, the chefs were characterised by a stronger subjective importance of work, a greater

MSX1 cooperates with histone H1b for inhibition of transcription and myogenesis.

PubMed

Lee, Hansol; Habas, Raymond; Abate-Shen, Cory

2004-06-11

During embryogenesis, differentiation of skeletal muscle is regulated by transcription factors that include members of the Msx homeoprotein family. By investigating Msx1 function in repression of myogenic gene expression, we identified a physical interaction between Msx1 and H1b, a specific isoform of mouse histone H1. We found that Msx1 and H1b bind to a key regulatory element of MyoD, a central regulator of skeletal muscle differentiation, where they induce repressed chromatin. Moreover, Msx1 and H1b cooperate to inhibit muscle differentiation in cell culture and in Xenopus animal caps. Our findings define a previously unknown function for "linker" histones in gene-specific transcriptional regulation.

Application of histone modification-specific interaction domains as an alternative to antibodies.

PubMed

Kungulovski, Goran; Kycia, Ina; Tamas, Raluca; Jurkowska, Renata Z; Kudithipudi, Srikanth; Henry, Chisato; Reinhardt, Richard; Labhart, Paul; Jeltsch, Albert

2014-11-01

Post-translational modifications (PTMs) of histones constitute a major chromatin indexing mechanism, and their proper characterization is of highest biological importance. So far, PTM-specific antibodies have been the standard reagent for studying histone PTMs despite caveats such as lot-to-lot variability of specificity and binding affinity. Herein, we successfully employed naturally occurring and engineered histone modification interacting domains for detection and identification of histone PTMs and ChIP-like enrichment of different types of chromatin. Our results demonstrate that histone interacting domains are robust and highly specific reagents that can replace or complement histone modification antibodies. These domains can be produced recombinantly in Escherichia coli at low cost and constant quality. Protein design of reading domains allows for generation of novel specificities, addition of affinity tags, and preparation of PTM binding pocket variants as matching negative controls, which is not possible with antibodies. © 2014 Kungulovski et al.; Published by Cold Spring Harbor Laboratory Press.

[Factors of working environment and process on non-ferrous metallurgy enterprises in Bashkortostan Republic and workers' occupational health].