Preparation and Biochemical Analysis of Classical Histone Deacetylases.
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ABSTRACT:
SUBMITTER: Villagra A
PROVIDER: S-EPMC5557005 | biostudies-other | 2016
REPOSITORIES: biostudies-other
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Project description:Transcriptional regulation in eukaryotes occurs within a chromatin setting, and is strongly influenced by the post-translational modification of histones, the building blocks of chromatin, such as methylation, phosphorylation and acetylation. Acetylation is probably the best understood of these modifications: hyperacetylation leads to an increase in the expression of particular genes, and hypoacetylation has the opposite effect. Many studies have identified several large, multisubunit enzyme complexes that are responsible for the targeted deacetylation of histones. The aim of this review is to give a comprehensive overview of the structure, function and tissue distribution of members of the classical histone deacetylase (HDAC) family, in order to gain insight into the regulation of gene expression through HDAC activity. SAGE (serial analysis of gene expression) data show that HDACs are generally expressed in almost all tissues investigated. Surprisingly, no major differences were observed between the expression pattern in normal and malignant tissues. However, significant variation in HDAC expression was observed within tissue types. HDAC inhibitors have been shown to induce specific changes in gene expression and to influence a variety of other processes, including growth arrest, differentiation, cytotoxicity and induction of apoptosis. This challenging field has generated many fascinating results which will ultimately lead to a better understanding of the mechanism of gene transcription as a whole.
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Project description:Reversible acetylation of histone and non-histone proteins is one of the most abundant post-translational modifications in eukaryotic cells. Protein acetylation and deacetylation are achieved by the antagonistic actions of two families of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). Aberrant protein acetylation, particularly on histones, has been related to cancer while abnormal expression of HDACs has been found in a broad range of cancer types. Therefore, HDACs have emerged as promising targets in cancer therapeutics, and the development of HDAC inhibitors (HDIs), a rapidly evolving area of clinical research. However, the contributions of specific HDACs to a given cancer type remain incompletely understood. The aim of this review is to summarize the current knowledge concerning the role of HDACs in cancer with special emphasis on what we have learned from the analysis of patient samples.
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Project description:The broad study of histone deacetylases in chemistry, biology and medicine relies on tool compounds to derive mechanistic insights. A phylogenetic analysis of class I and II histone deacetylases (HDACs) as targets of a comprehensive, structurally diverse panel of inhibitors revealed unexpected isoform selectivity even among compounds widely perceived as nonselective. The synthesis and study of a focused library of cinnamic hydroxamates allowed the identification of, to our knowledge, the first nonselective HDAC inhibitor. These data will guide a more informed use of HDAC inhibitors as chemical probes and therapeutic agents.
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Project description:Histone acetyltransferases and histone deacetylases regulate the acetylation of histones and transcription factors, and in doing so have major roles in the control of cell fate. Many recent results have indicated that their function is strictly regulated in cells through the modulation of their levels, activity and availability for interaction with specific transcription factors. In this review, we present the various molecular mechanisms that bring about this tight regulation and discuss how these regulatory events influence cellular responses to environmental changes.
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Project description:Cardiometabolic disease, emerging as a worldwide epidemic, is a combination of metabolic derangements leading to type 2 diabetes mellitus and cardiovascular disease. Genetic and environmental factors are linked through epigenetic mechanisms to the pathogenesis of cardiometabolic disease. Post-translational modifications of histone tails, including acetylation and deacetylation, epigenetically alter chromatin structure and dictate cell-specific gene expression patterns. The histone deacetylase family comprises 18 members that regulate gene expression by altering the acetylation status of nucleosomal histones and by functioning as nuclear transcriptional corepressors. Histone deacetylases regulate key aspects of metabolism, inflammation, and vascular function pertinent to cardiometabolic disease in a cell- and tissue-specific manner. Histone deacetylases also likely play a role in the metabolic memory of diabetes mellitus, an important clinical aspect of the disease. Understanding the molecular, cellular, and physiological functions of histone deacetylases in cardiometabolic disease is expected to provide insight into disease pathogenesis, risk factor control, and therapeutic development.
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Project description:ContextHistone deacetylases (HDACs) and histone acetyltransferases (HAT) have an important role in the regulation of gene transcription as well as in the development and function of CD4+Foxp3+ T regulatory (Treg) cells. Our group and others have reported that patients with autoimmune thyroid disease (AITD) show abnormalities in the levels and function of different Treg cell subsets.ObjectiveWe aimed to analyze the levels of expression of several HDACs and the Tip60 HAT in the thyroid gland and immune cells from patients with AITD.MethodsThe expression of HDAC1-11 and the Tip60 HAT, at RNA and protein levels, were determined in thyroid tissue from 20 patients with AITD and 10 healthy controls and these findings were correlated with clinical data. HDAC9 and Tip60 levels were also analyzed in thyroid cell cultures, stimulated or not with proinflammatory cytokines, as well as in different cell subsets from peripheral blood mononuclear cells.ResultsAltered expression of different HDACs was observed in thyroid tissue from AITD patients, including a significant increase in HDAC9, at RNA and protein levels. Likewise, HDAC9 expression was increased in peripheral blood mononuclear cells particularly in Treg cells in patients with AITD. In contrast, Tip60 expression was reduced in thyroid gland samples from patients with Hashimoto thyroiditis.ConclusionOur results indicate that HDAC expression is dysregulated in thyroid gland and immune cells from patients with AITD, suggesting involvement in the pathogenesis of this condition.
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Project description:Huntington's disease (HD) is a debilitating neurodegenerative condition with significant burdens on both patient and healthcare costs. Despite extensive research, treatment options for patients with this condition remain limited. Aberrant post-translational modification (PTM) of proteins is emerging as an important element in the pathogenesis of HD. These PTMs include acetylation, phosphorylation, methylation, sumoylation and ubiquitination. Several families of proteins are involved with the regulation of these PTMs. In this review, I discuss the current evidence linking aberrant PTMs and/or aberrant regulation of the cellular machinery regulating these PTMs to HD pathogenesis. Finally, I discuss the evidence suggesting that pharmacologically targeting one of these protein families the histone deacetylases may be of potential therapeutic benefit in the treatment of HD.
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Project description:Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferase p300, histone delactylases enzymes remained unknown. Here, we report the systematic evaluation of zinc- and nicotinamide adenine dinucleotide-dependent histone deacetylases (HDACs) for their ability to cleave ε-N-L-lactyllysine marks. Our screens identified HDAC1-3 and SIRT1-3 as delactylases in vitro. HDAC1-3 show robust activity toward not only K(L-la) but also K(D-la) and diverse short-chain acyl modifications. We further confirmed the de-L-lactylase activity of HDACs 1 and 3 in cells. Together, these data suggest that histone lactylation is installed and removed by regulatory enzymes as opposed to spontaneous chemical reactivity. Our results therefore represent an important step toward full characterization of this pathway's regulatory elements.
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Project description:Histone modifications have been shown to be crucial for secondary metabolism in various filamentous fungi. Here we studied the influence of histone acetylation on secondary metabolite production in the phytopathogenic fungus Fusarium fujikuroi, a known producer of several secondary metabolites including pigments and mycotoxins. Deletion of the classical HDACs FfHdF1, FfHdF2 and FfHdF3 indicated that FfHdF1 and FfHdF2 are major regulators of secondary metabolism, whereas FfHdF3 is involved in developmental processes but dispensable for secondary metabolite production in F. fujikuroi. Microarray analysis with the major HDAC FfHdF2 revealed differential regulation of several secondary metabolite gene clusters, subsequently verified by a combination of chemical and biological approaches. These results indicate that HDACs are responsible for gene silencing but also gene activation. Chromatin immunoprecipitation assays with M-NM-^TffhdF2 revealed significant alterations regarding the acetylation state in the landscape of secondary metabolite gene clusters thereby providing insights into the regulatory mechanism. In addition, the class I HDAC FfHdF1 also has major impact on secondary metabolism in F. fujikuroi. Furthermore, deletion of both ffhdF1 and ffhdF2 resulted in de-repression of secondary metabolites under normally repressing conditions. Thus, manipulation of HDAC encoding genes might provide a powerful tool for the activation of cryptic secondary metabolites. Investigation of whole genome gene expression of the Fusarium fujikuroi wild type IMI58289, M-NM-^TffhdF2 mutant under nitrogen starvation and nitrogen sufficient conditions. In this study we hybridized in total 12 microarrays using total RNA recovered from a wild-type culture of F. fujikuroi IMI58289 and M-NM-^TffhdF2 mutant culture. All cultures were grown on a 6 mM Gln (10%) and a 60 mM Gln medium (100%). For each combination of culture and medium a biological replicate was created. Each chip measures the expression level of 14,397 genes from F. fujikuroi IMI58289 with eight 60-mer probes.
2013-10-05 | E-GEOD-43768 | biostudies-arrayexpress
Project description:Histone deacetylase inhibitors (HDACis) have fascinated researchers in almost all fields of oncology for many years owing to their pleiotropic effects on nearly every aspect of cancer biology. Since the approval of the first HDACi vorinostat for the treatment of cutaneous T-cell leukemia in 2006, more than a hundred clinical trials have been initiated with a HDACi as a single agent or in combination therapy. Although a number of epigenetic and nonepigenetic molecular mechanisms of action have been proposed, biomarkers for response prediction and patient selection are still lacking. One of the inherent problems in the field of HDACis is their 'reverse' history of drug development: these compounds reached clinical application at an early stage, before the biology of their targets, HDAC1-11, was sufficiently understood. This review summarizes the current knowledge on the human family of HDACs as drug targets in pediatric and adult brain tumors, the efficacy and molecular action of HDACis in preclinical models, as well as the current status of the clinical development of these compounds in the field of neuro-oncology.
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