Chromatin modifiers and remodellers: regulators of cellular differentiation

Chen, Taiping; Dent, Sharon Y.R.

doi:10.1038/nrg3607

Cited by 572 publications

(537 citation statements)

References 142 publications

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“…Trimethylation of H3K4 (H3K4me3) is correlated with active promoters, whereas many transcriptionally silent promoters are enriched for H3K27me3 and H3K9me3 (Table 1) [16]. Some histone methylation marks can also delineate enhancer regions (H3K4me1) or actively transcribed gene bodies (H3K36me3) [17]. Some genes can also have a "poised" status where bivalent histone modifications are present.…”

Section: Histone Tail Modificationmentioning

confidence: 99%

Resetting the epigenome for heart regeneration.

Quaife-Ryan

Sim

Porrello

et al. 2016

Seminars in Cell & Developmental Biology

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In contrast to adults, recent evidence suggests that neonatal mice are able to regenerate following cardiac injury. This regenerative capacity is reliant on robust induction of cardiomyocyte proliferation, which is required for faithful regeneration of the heart following injury. However, cardiac regenerative potential is lost as cardiomyocytes mature and permanently withdraw from the cell cycle shortly after birth. Recently, a handful of factors responsible for the regenerative disparity between the adult and neonatal heart have been identified, but the proliferative response of adult cardiomyoctes following modulation of these factors rarely reaches neonatal levels. The inefficient re-induction of proliferation in adult cardiomyocytes may be due to the epigenetic landscape, which drastically changes during cardiac development and maturation. In this review, we provide an overview of the role of epigenetic modifiers in developmental processes related to cardiac regeneration. We propose an epigentic framework for heart regeneration whereby adult cardiomyocyte identity requires resetting to a neonatal-like state to facilitate cell cycle re-entry and regeneration following cardiac injury.

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Section: Histone Tail Modificationmentioning

confidence: 99%

Resetting the epigenome for heart regeneration.

Quaife-Ryan

Sim

Porrello

et al. 2016

Seminars in Cell & Developmental Biology

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“…The present study provides the mechanistic basis of a deacetylase-independent function of HDAC3 as a scaffold to recruit methyltransferase components of PRC2 (polycomb repressive complex 2) to epigenetically silence TGF-␤1. Repressor complex-mediated gene silencing is critical to maintain cellular identity of differentiated cells through multiple divisions (78). Recent evidence suggests that PRC2-mediated epigenetic silencing is maintained for many cell generations.…”

Section: Cdh5komentioning

confidence: 99%

Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field Development

Lewandowski

Janardhan

Trivedi

2015

Journal of Biological Chemistry

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Background: Histone-modifying genes play critical roles in the pathogenesis of human congenital heart disease. Results: HDAC3 recruits PRC2 complex to mediate epigenetic silencing of TGF-␤1 in a deacetylase-independent manner within second heart field progenitor cells. Conclusion: HDAC3-mediated epigenetic silencing of TGF-␤1 is required for normal heart development. Significance: This is the first report of HDAC-mediated epigenetic regulation of second heart field development.

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“…Mutations in chromatin modifiers are frequent occurrences in a number of cancers and are often associated with aberrant cell fate decisions (1)(2)(3). These lesions are particularly frequent events in non-Hodgkin B-cell Lymphoma.…”

Section: Introductionmentioning

confidence: 99%

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

Brach

Johnston-Blackwell

Drew

et al. 2017

Molecular Cancer Therapeutics

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The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2. Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model. Previous work has demonstrated that cotreatment with tazemetostat and glucocorticoid receptor agonists lead to a synergistic antiproliferative effect in both mutant and wild-type backgrounds, which may provide clues to the mechanism of action of EZH2 inhibition in WT-EZH2 models. Multiple agents that inhibit the B-cell receptor pathway (e.g., ibrutinib) were found to have synergistic benefit when combined with tazemetostat in both mutant and WT-EZH2 backgrounds of diffuse large B-cell lymphomas (DLBCL). The relationship between B-cell activation and EZH2 inhibition is consistent with the proposed role of EZH2 in B-cell maturation. To further support this, we observe that cell lines treated with tazemetostat show an increase in the B-cell maturation regulator, PRDM1/BLIMP1, and gene signatures corresponding to more advanced stages of maturation. These findings suggest that EZH2 inhibition in both mutant and wild-type backgrounds leads to increased Bcell maturation and a greater dependence on B-cell activation signaling.

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Chromatin modifiers and remodellers: regulators of cellular differentiation

Cited by 572 publications

References 142 publications

Resetting the epigenome for heart regeneration.

Resetting the epigenome for heart regeneration.

Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field Development

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

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