Histone acetylation: a switch between repressive and permissive chromatin

Eberharter, Anton; Becker, Peter B.

doi:10.1093/embo-reports/kvf053

Cited by 838 publications

(660 citation statements)

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“…While histone acetylation events contribute to gene activation, the patterns of acetylation are diverse and distinct depending on the regulatory loci [5–7]. A comprehensive mapping of 18 histone acetylation marks in CD4 + T cells revealed that H3K9ac, H3K18ac, and H3K27ac are mainly located in regions surrounding the transcription start sites (TSS), whereas H4K8ac is elevated in promoter and transcribed regions of active genes [8,9].…”

Section: Introductionmentioning

confidence: 99%

Loci-specific histone acetylation profiles associated with transcriptional coactivator p300 during early myoblast differentiation

et al. 2018

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Molecular regulation of stem cell differentiation is exerted through both genetic and epigenetic determinants over distal regulatory or enhancer regions. Understanding the mechanistic action of active or poised enhancers is therefore imperative for control of stem cell differentiation. Based on the genome-wide co-occurrence of different epigenetic marks in committed proliferating myoblasts, we have previously generated a 14-state chromatin state model to profile rexinoid-responsive histone acetylation in early myoblast differentiation. Here, we delineate the functional mode of transcription regulators during early myogenic differentiation using genome-wide chromatin state association. We define a role of transcriptional coactivator p300, when recruited by muscle master regulator MyoD, in the establishment and regulation of myogenic loci at the onset of myoblast differentiation. In addition, we reveal an enrichment of loci-specific histone acetylation at p300 associated active or poised enhancers, particularly when enlisted by MyoD. We provide novel molecular insights into the regulation of myogenic enhancers by p300 in concert with MyoD. Our studies present a valuable aptitude for driving condition-specific chromatin state or enhancers pharmacologically to treat muscle-related diseases and for the identification of additional myogenic targets and molecular interactions for therapeutic development.Abbreviations: MRF: Muscle regulatory factor; HAT: Histone acetyltransferase; CBP: CREB-binding protein; ES: Embryonic stem; ATCC: American type culture collection; DM: Differentiation medium; DMEM: Dulbecco’s Modified Eagle Medium; GM: Growth medium; GO: Gene ontology; GREAT: Genomic regions enrichment of annotations tool; FPKM: Fragments per kilobase of transcript per million; GEO: Gene expression omnibus; MACS: Model-based analysis for ChIP-seq

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Section: Introductionmentioning

confidence: 99%

Loci-specific histone acetylation profiles associated with transcriptional coactivator p300 during early myoblast differentiation

et al. 2018

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“…MLL catalyzes di-(H3K4me2) and trimethylation of lysine 4 of histone H3 (H3K4me3) (Hess, 2004). These histone modifications as well as acetylation of histone H3 (H3K9K14ac) and H4K16ac are associated with transcriptionally active regions (Eberharter and Becker, 2002;Santos-Rosa et al, 2002;Dion et al, 2005). Conversely, trimethylation of lysine 9 of histone H3 (H3K9me3) and trimethylation of lysine 27 of histone H3 (H3K27me3) are repressive marks.…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

et al. 2010

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MOZ and MLL, encoding a histone acetyltransferase (HAT) and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. In MOZ (MOnocytic leukemia Zinc-finger protein)/CBP-or mixed lineage leukemia (MLL)-rearranged leukemias, abnormal levels of HOX transcription factors have been found to be critical for leukemogenesis. We show that MOZ and MLL cooperate to regulate these key genes in human cord blood CD34 þ cells. These chromatinmodifying enzymes interact, colocalize and functionally cooperate, and both are recruited to multiple HOX promoters. We also found that WDR5, an adaptor protein essential for lysine 4 trimethylation of histone H3 (H3K4me3) by MLL, colocalizes and interacts with MOZ. We detected the binding of the HAT MOZ to H3K4me3, thus linking histone methylation to acetylation. In CD34 þ cells, depletion of MLL causes release of MOZ from HOX promoters, which is correlated to defective histone activation marks, leading to repression of HOX gene expression and alteration of commitment of CD34 þ cells into myeloid progenitors. Thus, our results unveil the role of the interaction between MOZ and MLL in CD34 þ cells in which both proteins have a critical role in hematopoietic cell-fate decision, suggesting a new molecular mechanism by which MOZ or MLL deregulation leads to leukemogenesis.

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“…It is widely accepted that this densely packed DNA structure is maintained by the enzymatic activity of the histone deacetylases (HDAC), which maintain the histones in a deacetylated state. Deacetylated histones prevent the binding of transcription factors and suppress the transcriptional machinery [1][2][3]. Inhibition of HDACs results in hyper-acetylation and unravelling of DNA permitting gene activation.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

et al. 2007

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Aims/hypothesis The immune-mediated elimination of pancreatic beta cells in type 1 diabetes involves release of cytotoxic cytokines such as IL-1β and IFNγ, which induce beta cell death in vitro by mechanisms that are both dependent and independent of nitric oxide (NO). Nuclear factor kappa B (NFκB) is a critical signalling molecule in inflammation and is required for expression of the gene encoding inducible NO synthase (iNOS) and of proapoptotic genes. NFκB has recently been shown to associate with chromatin-modifying enzymes histone acetyltransferases and histone deacetylases (HDAC), and positive effects of HDAC inhibition have been obtained in several inflammatory diseases. Thus, the aim of this study was to investigate whether HDAC inhibition protects beta cells against cytokine-induced toxicity. Materials and methods The beta cell line, INS-1, or intact rat islets were precultured with HDAC inhibitors suberoylanilide hydroxamic acid or trichostatin A in the absence or presence of IL-1β and IFNγ. Effects on insulin secretion and NO formation were measured by ELISA and Griess reagent, respectively. iNOS levels and NFκB activity were measured by immunoblotting and by immunoblotting combined with electrophoretic mobility shift assay, respectively. Viability was analysed by 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and apoptosis by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and histone-DNA complex ELISA. Results HDAC inhibition reduced cytokine-mediated decrease in insulin secretion and increase in iNOS levels, NO formation and apoptosis. IL-1β induced a bi-phasic phosphorylation of inhibitor protein kappa Bα (IκBα) with the 2nd peak being sensitive to HDAC inhibition. No effect was seen on IκBα degradation and NFκB DNA binding. Conclusions/interpretation HDAC inhibition prevents cytokine-induced beta cell apoptosis and impaired beta cell function associated with a downregulation of NFκB transactivating activity.

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Histone acetylation: a switch between repressive and permissive chromatin

Cited by 838 publications

References 77 publications

Loci-specific histone acetylation profiles associated with transcriptional coactivator p300 during early myoblast differentiation

Loci-specific histone acetylation profiles associated with transcriptional coactivator p300 during early myoblast differentiation

Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells

Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

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