The Chromatin Remodeling Complex Chd4/NuRD Controls Striated Muscle Identity and Metabolic Homeostasis

Arco, Pablo Gómez-del; Perdiguero, Eusebio; Yunes-Leites, Paula Sofía; Acı́n-Pérez, Rebeca; Zeini, Miriam; García-Gómez, Antonio; Sreenivasan, Krishnamoorthy; Jiménez-Alcázar, Miguel; Segalés, Jessica; López-Maderuelo, Dolores; Ornes, Beatriz C.; Jiménez-Borreguero, Luis Jesús; D’Amato, Gaetano; Enshell-Seijffers, David; Morgan, Bruce; Georgopoulos, Katia; Islam, Abul B.M.M.K.; Braun, Thomas; Pompa, José Luis de la; Kim, Johnny; Enrı́quez, José Antonio; Ballestar, Esteban; Muñoz‐Cánoves, Pura; Redondo, Juan Miguel

doi:10.1016/j.cmet.2016.04.008

Cited by 59 publications

(79 citation statements)

References 44 publications

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“…NuRD is highly conserved amongst metazoans and has been shown to play important roles in cell fate decisions in a wide array of systems (Denslow & Wade, ; Signolet & Hendrich, ). For example, in embryonic stem (ES) cells, NuRD controls nucleosome positioning at regulatory sequences to finely tune gene expression (Reynolds et al , ; Bornelöv et al , ), and in somatic lineages, NuRD activity has been shown to prevent inappropriate expression of lineage‐specific genes to ensure fidelity of somatic lineage decisions (Denner & Rauchman, ; Knock et al , ; Gomez‐Del Arco et al , ; Loughran et al , ). It was recently demonstrated that this is achieved in both ES cells and B‐cell progenitors by restricting access of transcription factors to regulatory sequences (Liang et al , ; Loughran et al , ; Bornelöv et al , ).…”

Section: Introductionmentioning

confidence: 99%

The Nucleosome Remodelling and Deacetylation complex suppresses transcriptional noise during lineage commitment

et al. 2019

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Multiprotein chromatin remodelling complexes show remarkable conservation of function amongst metazoans, even though components present in invertebrates are often found as multiple paralogous proteins in vertebrate complexes. In some cases, these paralogues specify distinct biochemical and/or functional activities in vertebrate cells. Here, we set out to define the biochemical and functional diversity encoded by one such group of proteins within the mammalian Nucleosome Remodelling and Deacetylation (Nu RD ) complex: Mta1, Mta2 and Mta3. We find that, in contrast to what has been described in somatic cells, MTA proteins are not mutually exclusive within embryonic stem (ES) cell Nu RD and, despite subtle differences in chromatin binding and biochemical interactions, serve largely redundant functions. ES cells lacking all three MTA proteins exhibit complete Nu RD loss of function and are viable, allowing us to identify a previously unreported function for Nu RD in reducing transcriptional noise, which is essential for maintaining a proper differentiation trajectory during early stages of lineage commitment.

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Section: Introductionmentioning

confidence: 99%

The Nucleosome Remodelling and Deacetylation complex suppresses transcriptional noise during lineage commitment

et al. 2019

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“…Thus, the increased expression after insulin treatment could possibly impact development. CHD4 , which represents the main component of the nucleosome remodeling and the deacetylase complex that is involved in epigenetic transcriptional repression (Gomez‐Del Arco et al, ; Singh et al, ), was hypomethylated and upregulated in both insulin‐treated groups. The HIST1H1C gene encodes a histone H1 subtype that is involved in the dynamics of the chromatin structure (Clausell, Happel, Hale, Doenecke, & Beato, ) and has a function in organizing the epigenetic landscape (Sadakierska‐Chudy, Kostrzewa, & Filip, ).…”

Section: Discussionmentioning

confidence: 99%

DNA methylation pattern of bovine blastocysts associated with hyperinsulinemia in vitro

Laskowski

Humblot

Sirard

et al. 2018

Molecular Reproduction Devel

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Insulin functions as a regulator of metabolism and plays an important role in reproduction. Hyperinsulinemia is often observed in patients with obesity and diabetes type 2 and is known to impair fertility, but the underlying molecular mechanisms are only partly understood. Metabolic programming through epigenetic mechanisms such as DNA methylation during embryonic development can lead to health implications for the offspring later in life. Our aim was to study the potential effect of hyperinsulinemia on gene expression and DNA methylation of embryos by adding insulin (0.1 µg/ml = INS0.1 or 10 µg/ml = INS10) during in vitro oocyte maturation by using the EmbryoGENE DNA methylation array for a study of the bovine epigenome. Our results showed significant differences between blastocysts originating from insulin-treated oocytes compared with untreated control blastocysts. In total, 13,658 and 12,418 probes were differentially methylated (DM) in INS0.1 and INS10, respectively, with an overlap of 3,233 probes in the DM regions (DMR) for both insulin groups. Genes related to pathways such as lipid metabolism, growth and proliferation, mitochondrial function, and oxidative stress responses were influenced at both the epigenetic and transcriptomic levels. In addition, imprinted genes and genes with functions in the epigenetic machinery were among the DMRs. This study identified DMRs correlated to differential expression of genes involved in metabolic regulation and should help to improve our knowledge of the underlying molecular mechanisms of metabolic imbalance.

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“…For example, the role of cytokine/chemokine signaling and integrins/extracellular matrix, as identified in our pathway analysis of the transcriptome data, remains to be determined. Nevertheless, the current study adds to a growing list of epigenetic factors that regulate heart physiology such as the PRC2 polycomb complex and the NuRD chromatin-remodeling complex [38–41]. …”

Section: Discussionmentioning

confidence: 99%

BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility

Willis

Holley

Wang

et al. 2017

Journal of Molecular and Cellular Cardiology

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Rationale The contractile dysfunction that underlies heart failure involves perturbations in multiple biological processes ranging from metabolism to electrophysiology. Yet the epigenetic mechanisms that are altered in this disease state have not been elucidated. SWI/SNF chromatin-remodeling complexes are plausible candidates based on mouse knockout studies demonstrating a combined requirement for the BRG1 and BRM catalytic subunits in adult cardiomyocytes. Brg1/Brm double mutants exhibit metabolic and mitochondrial defects and are not viable although their cause of death has not been ascertained. Objective To determine the cause of death of Brg1/Brm double-mutant mice, to test the hypothesis that BRG1 and BRM are required for cardiac contractility, and to identify relevant downstream target genes. Methods and results A tamoxifen-inducible gene-targeting strategy utilizing αMHC-Cre-ERT was implemented to delete both SWI/SNF catalytic subunits in adult cardiomyocytes. Brg1/Brm double-mutant mice were monitored by echocardiography and electrocardiography, and they underwent rapidly progressive ventricular dysfunction including conduction defects and arrhythmias that culminated in heart failure and death within 3 weeks. Mechanistically, BRG1/BRM repressed c-Myc expression, and enforced expression of a DOX- inducible c-MYC trangene in mouse cardiomyocytes phenocopied the ventricular conduction defects observed in Brg1/Brm double mutants. BRG1/BRM and c-MYC had opposite effects on the expression of cardiac conduction genes, and the directionality was consistent with their respective loss- and gain-of-function phenotypes. To support the clinical relevance of this mechanism, BRG1/BRM occupancy was diminished at the same target genes in human heart failure cases compared to controls, and this correlated with increased c-MYC expression and decreased CX43 and SCN5A expression. Conclusion BRG1/BRM and c-MYC have an antagonistic relationship regulating the expression of cardiac conduction genes that maintain contractility, which is reminiscent of their antagonistic roles as a tumor suppressor and oncogene in cancer.

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The Chromatin Remodeling Complex Chd4/NuRD Controls Striated Muscle Identity and Metabolic Homeostasis

Cited by 59 publications

References 44 publications

The Nucleosome Remodelling and Deacetylation complex suppresses transcriptional noise during lineage commitment

The Nucleosome Remodelling and Deacetylation complex suppresses transcriptional noise during lineage commitment

DNA methylation pattern of bovine blastocysts associated with hyperinsulinemia in vitro

BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility

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