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

Pablo Gómez-Del Arco, Eusebio Perdiguero, Paula Sofia Yunes-Leites, Rebeca Acín-Pérez, Miriam Zeini, Antonio Garcia-Gomez, Krishnamoorthy Sreenivasan, Miguel Jiménez-Alcázar, Jessica Segalés, Dolores López-Maderuelo, Beatriz Ornés, Luis Jesús Jiménez-Borreguero, Gaetano D'Amato, David Enshell-Seijffers, Bruce Morgan, Katia Georgopoulos, Abul B.M.M.K. Islam, Thomas Braun, José Luis De La Pompa, Johnny KimJosé A. Enriquez, Esteban Ballestar, Pura Muñoz-Cánoves, Juan Miguel Redondo

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Heart muscle maintains blood circulation, while skeletal muscle powers skeletal movement. Despite having similar myofibrilar sarcomeric structures, these striated muscles differentially express specific sarcomere components to meet their distinct contractile requirements. The mechanism responsible is still unclear. We show here that preservation of the identity of the two striated muscle types depends on epigenetic repression of the alternate lineage gene program by the chromatin remodeling complex Chd4/NuRD. Loss of Chd4 in the heart triggers aberrant expression of the skeletal muscle program, causing severe cardiomyopathy and sudden death. Conversely, genetic depletion of Chd4 in skeletal muscle causes inappropriate expression of cardiac genes and myopathy. In both striated tissues, mitochondrial function was also dependent on the Chd4/NuRD complex. We conclude that an epigenetic mechanism controls cardiac and skeletal muscle structural and metabolic identities and that loss of this regulation leads to hybrid striated muscle tissues incompatible with life.

Original languageEnglish
Pages (from-to)881-892
Number of pages12
JournalCell Metabolism
Volume23
Issue number5
DOIs
StatePublished - 10 May 2016

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.

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