title: The Chromatin Remodeling Complex Chd4/NuRD Controls Striated Muscle Identity and Metabolic Homeostasis.
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.
authors.affiliation: Gene Regulation in Cardiovascular Remodelling & Inflammation laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain; Department of Molecular Biology, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain. Electronic address: pablo.gomez@uam.es.
authors.forename: Pablo
authors.initials: P
authors.lastname: Gómez-Del Arco
authors.affiliation: Department of Experimental & Health Sciences, University Pompeu Fabra (UPF)/CIBERNED/ICREA, Barcelona 08003, Spain.
authors.forename: Eusebio
authors.initials: E
authors.lastname: Perdiguero
authors.affiliation: Gene Regulation in Cardiovascular Remodelling & Inflammation laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain.
authors.forename: Paula Sofia
authors.initials: PS
authors.lastname: Yunes-Leites
authors.affiliation: Physiopathology of the Myocardium Programme, CNIC, Madrid 28029, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Acín-Pérez
authors.affiliation: Gene Regulation in Cardiovascular Remodelling & Inflammation laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Zeini
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona 08908, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Garcia-Gomez
authors.affiliation: Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
authors.forename: Krishnamoorthy
authors.initials: K
authors.lastname: Sreenivasan
authors.affiliation: Gene Regulation in Cardiovascular Remodelling & Inflammation laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Jiménez-Alcázar
authors.affiliation: Department of Experimental & Health Sciences, University Pompeu Fabra (UPF)/CIBERNED/ICREA, Barcelona 08003, Spain.
authors.forename: Jessica
authors.initials: J
authors.lastname: Segalés
authors.affiliation: Gene Regulation in Cardiovascular Remodelling & Inflammation laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: López-Maderuelo
authors.affiliation: Gene Regulation in Cardiovascular Remodelling & Inflammation laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Ornés
authors.affiliation: Department of Epidemiology, Atherotrombosis and Image, CNIC, Madrid 28029, Spain; Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Madrid 28013, Spain.
authors.forename: Luis Jesús
authors.initials: LJ
authors.lastname: Jiménez-Borreguero
authors.affiliation: Intercellular Signaling in Cardiovascular Development & Disease Laboratory, CNIC, Madrid 28029, Spain.
authors.forename: Gaetano
authors.initials: G
authors.lastname: D'Amato
authors.affiliation: Faculty of Medicine in the Galilee, Bar-llan University, Safed 1589, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Enshell-Seijffers
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Morgan
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Katia
authors.initials: K
authors.lastname: Georgopoulos
authors.affiliation: Department of Genetic Engineering & Biotechnology, University of Dhaka, Dhaka 1000, Bangladesh.
authors.forename: Abul B M M K
authors.initials: AB
authors.lastname: Islam
authors.affiliation: Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.affiliation: Intercellular Signaling in Cardiovascular Development & Disease Laboratory, CNIC, Madrid 28029, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: de la Pompa
authors.affiliation: Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
authors.forename: Johnny
authors.initials: J
authors.lastname: Kim
authors.affiliation: Physiopathology of the Myocardium Programme, CNIC, Madrid 28029, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Enriquez
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona 08908, Spain.
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
authors.affiliation: Department of Experimental & Health Sciences, University Pompeu Fabra (UPF)/CIBERNED/ICREA, Barcelona 08003, Spain; Tissue Regeneration laboratory, CNIC, Madrid 28029, Spain.
authors.forename: Pura
authors.initials: P
authors.lastname: Muñoz-Cánoves
authors.affiliation: Gene Regulation in Cardiovascular Remodelling & Inflammation laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid 28029, Spain. Electronic address: jmredondo@cnic.es.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Redondo
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D042002:Chromatin Assembly and Disassembly; D018899:CpG Islands / Q000235:genetics; D004265:DNA Helicases / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology; D006706:Homeostasis; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism*; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism; D054792:Muscle, Striated / Q000196:embryology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding
chemical_list: D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; C509277:Mi-2beta protein, mouse; D004265:DNA Helicases