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 Kim; José A. Enriquez; Esteban Ballestar; Pura Muñoz-Cánoves; Juan Miguel Redondo

doi:10.1016/j.cmet.2016.04.008

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

Bar-Ilan University - Azrieli Faculty of Medicine

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51 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 language	English
Pages (from-to)	881-892
Number of pages	12
Journal	Cell Metabolism
Volume	23
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2016.04.008
State	Published - 10 May 2016

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.

Funding

We thank Drs. Richard Harvey (University of Sydney, Australia) and Michael Schneider (Imperial College, London, UK) for providing Nkx2.5 cre/+ and α-MHC cre/+ transgenic lines, respectively, Dr. S. Bartlett for English editing, and Gemma Benito and Ana Guío for technical assistance. J.M.R. is supported by the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía y Competitividad; SAF 2012 34296 and SAF 2015 63633-R), the Spanish Ministry of Health (Ministerio de Sanidad y Consumo) Red de Investigación Cardiovascular (RIC; grant RD06/0042/0022), and the Fundación La Marató TV3 (264/C/2012). The RIC also supports J.L.P. (RD12/0042/0005) and L.J.J.-B. (RD12/0042/0056). RIC grants are partially funded by FEDER funds. P.M.-C., J.A.E., and J.L.P. are supported by SAF2012-38547, SAF2015-67369-R, SAF2012-1207, and SAF2013-45543-R, respectively. E.P. and P.M.-C. were also supported by SAF2015-67369-R. NGS experiments were performed at the CNIC Genomics Unit. IF of adult hearts was performed at the Advanced Fluorescence Microscopy Unit of (IBMB-CSIC) Barcelona. The CNIC is supported by the Spanish Ministry of Economy and Competitiveness and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). R.A.-P. was supported by a Ramón y Cajal grant and is a holder of a Marie Curie grant (RA-P:UEO/MCA1108). M.Z. was a holder of a Marie Curie Outgoing International Fellowship (MOIF-CT-2006-039327), and P.G.A. was supported by a Ramón y Cajal grant from the Spanish Ministry of Education, Science and Sport.

Funders	Funder number
Ministerio de Sanidad y Consumo	RD06/0042/0022
Pro-CNIC Foundation
Fundació la Marató de TV3	264/C/2012
Ministerio de Educación, Cultura y Deporte
Ministerio de Economía y Competitividad	SAF 2012 34296, MOIF-CT-2006-039327, SAF 2015 63633-R, UEO/MCA1108, SEV-2015-0505
European Regional Development Fund	SAF2015-67369-R
Consejería de Salud y Familias, Junta de Andalucía

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Gómez-Del Arco, P., Perdiguero, E., Yunes-Leites, P. S., Acín-Pérez, R., Zeini, M., Garcia-Gomez, A., Sreenivasan, K., Jiménez-Alcázar, M., Segalés, J., López-Maderuelo, D., Ornés, B., Jiménez-Borreguero, L. J., D'Amato, G., Enshell-Seijffers, D., Morgan, B., Georgopoulos, K., Islam, A. B. M. M. K., Braun, T., De La Pompa, J. L., ... Redondo, J. M. (2016). The Chromatin Remodeling Complex Chd4/NuRD Controls Striated Muscle Identity and Metabolic Homeostasis. Cell Metabolism, 23(5), 881-892. https://doi.org/10.1016/j.cmet.2016.04.008

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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.",

author = "{G{\'o}mez-Del Arco}, Pablo and Eusebio Perdiguero and Yunes-Leites, {Paula Sofia} and Rebeca Ac{\'i}n-P{\'e}rez and Miriam Zeini and Antonio Garcia-Gomez and Krishnamoorthy Sreenivasan and Miguel Jim{\'e}nez-Alc{\'a}zar and Jessica Segal{\'e}s and Dolores L{\'o}pez-Maderuelo and Beatriz Orn{\'e}s and Jim{\'e}nez-Borreguero, {Luis Jes{\'u}s} and Gaetano D'Amato and David Enshell-Seijffers and Bruce Morgan and Katia Georgopoulos and Islam, {Abul B.M.M.K.} and Thomas Braun and {De La Pompa}, {Jos{\'e} Luis} and Johnny Kim and Enriquez, {Jos{\'e} A.} and Esteban Ballestar and Pura Mu{\~n}oz-C{\'a}noves and Redondo, {Juan Miguel}",

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doi = "10.1016/j.cmet.2016.04.008",

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Gómez-Del Arco, P, Perdiguero, E, Yunes-Leites, PS, Acín-Pérez, R, Zeini, M, Garcia-Gomez, A, Sreenivasan, K, Jiménez-Alcázar, M, Segalés, J, López-Maderuelo, D, Ornés, B, Jiménez-Borreguero, LJ, D'Amato, G, Enshell-Seijffers, D, Morgan, B, Georgopoulos, K, Islam, ABMMK, Braun, T, De La Pompa, JL, Kim, J, Enriquez, JA, Ballestar, E, Muñoz-Cánoves, P & Redondo, JM 2016, 'The Chromatin Remodeling Complex Chd4/NuRD Controls Striated Muscle Identity and Metabolic Homeostasis', Cell Metabolism, vol. 23, no. 5, pp. 881-892. https://doi.org/10.1016/j.cmet.2016.04.008

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T1 - The Chromatin Remodeling Complex Chd4/NuRD Controls Striated Muscle Identity and Metabolic Homeostasis

AU - Gómez-Del Arco, Pablo

AU - Perdiguero, Eusebio

AU - Yunes-Leites, Paula Sofia

AU - Acín-Pérez, Rebeca

AU - Zeini, Miriam

AU - Garcia-Gomez, Antonio

AU - Sreenivasan, Krishnamoorthy

AU - Jiménez-Alcázar, Miguel

AU - Segalés, Jessica

AU - López-Maderuelo, Dolores

AU - Ornés, Beatriz

AU - Jiménez-Borreguero, Luis Jesús

AU - D'Amato, Gaetano

AU - Enshell-Seijffers, David

AU - Morgan, Bruce

AU - Georgopoulos, Katia

AU - Islam, Abul B.M.M.K.

AU - Braun, Thomas

AU - De La Pompa, José Luis

AU - Kim, Johnny

AU - Enriquez, José A.

AU - Ballestar, Esteban

AU - Muñoz-Cánoves, Pura

AU - Redondo, Juan Miguel

PY - 2016/5/10

Y1 - 2016/5/10

N2 - 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.

AB - 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.

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SN - 1550-4131

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

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