Chromatin-wide and transcriptome profiling integration uncovers p38α MAPK as a global regulator of skeletal muscle differentiation

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  • dc.contributor.author Segalés Dalmau, Jessicaca
  • dc.contributor.author Islam, Abul, 1978-ca
  • dc.contributor.author Kumar, Roshanca
  • dc.contributor.author Liu, Qi-Caica
  • dc.contributor.author Sousa-Victor, Pedroca
  • dc.contributor.author Dilworth, F. Jeffreyca
  • dc.contributor.author Ballestar, Estebanca
  • dc.contributor.author Perdiguero, Eusebio, 1968-ca
  • dc.contributor.author Muñoz Cánoves, Pura, 1962-ca
  • dc.date.accessioned 2016-11-28T16:32:59Z
  • dc.date.available 2016-11-28T16:32:59Z
  • dc.date.issued 2016ca
  • dc.description.abstract Background: Extracellular stimuli induce gene expression responses through intracellular signaling mediators. The p38 signaling pathway is a paradigm of the mitogen-activated protein kinase (MAPK) family that, although originally identified as stress-response mediator, contributes to establishing stem cell differentiation fates. p38α is central for induction of the differentiation fate of the skeletal muscle stem cells (satellite cells) through not fully characterized mechanisms. Methods: To investigate the global gene transcription program regulated by p38α during satellite cell differentiation (myogenesis), and to specifically address whether this regulation occurs through direct action of p38α on gene promoters, we performed a combination of microarray gene expression and genome-wide binding analyses. For experimental robustness, two myogenic cellular systems with genetic and chemical loss of p38α function were used: (1) satellite cells derived from mice with muscle-specific deletion of p38α, and (2) the C2C12 murine myoblast cell line cultured in the absence or presence of the p38α/β inhibitor SB203580. Analyses were performed at cell proliferation and early differentiation stages. Results: We show that p38α binds to a large set of active promoters during the transition of myoblasts from proliferation to differentiation stages. p38α-bound promoters are enriched with binding motifs for several transcription factors, with Sp1, Tcf3/E47, Lef1, FoxO4, MyoD, and NFATc standing out in all experimental conditions. p38α association with chromatin correlates very well with high levels of transcription, in agreement with its classical function as an activator of myogenic differentiation. Interestingly, p38α also associates with genes repressed at the onset of differentiation, thus highlighting the relevance of p38-dependent chromatin regulation for transcriptional activation and repression during myogenesis. Conclusions: These results uncover p38α association and function on chromatin at novel classes of target genes during skeletal muscle cell differentiation. This is consistent with this MAPK isoform being a transcriptional regulator.
  • dc.description.sponsorship The authors acknowledge funding from MINECO, Spain (SAF2012-38547, PLE2009-0124, SAF2015-67369-R, "María de Maeztu" Programme for Units of Excellence in R&D MDM-2014-0370), AFM, MDA, DDP-Netherlands, E-RARE, Fundació Marató TV3 and EU-FP7 (Myoage, Optistem and Endostem). JS is recipient of a Juan de la Cierva postdoctoral fellowship.
  • dc.format.mimetype application/pdfca
  • dc.identifier.citation Segalés Dalmau J, Islam A, Kumar R, Liu Q-C, Sousa-Victor, P, Dilworth FJ et al. Chromatin-wide and transcriptome profiling integration uncovers p38α MAPK as a global regulator of skeletal muscle differentiation. Skeletal Muscle. 2016;6(1):9. DOI: 10.1186/s13395-016-0074-xca
  • dc.identifier.doi http://dx.doi.org/10.1186/s13395-016-0074-x
  • dc.identifier.issn 2044-5040ca
  • dc.identifier.uri http://hdl.handle.net/10230/27624
  • dc.language.iso engca
  • dc.publisher BioMed Centralca
  • dc.relation.ispartof Skeletal Muscle. 2016;6(1):9
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/223576
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2012-38547
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/PLE2009-0124
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-67369-R
  • dc.rights © 2016 Segalés et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.ca
  • dc.rights.accessRights info:eu-repo/semantics/openAccessca
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.other Transcripció genètica--Regulació
  • dc.title Chromatin-wide and transcriptome profiling integration uncovers p38α MAPK as a global regulator of skeletal muscle differentiationca
  • dc.type info:eu-repo/semantics/articleca
  • dc.type.version info:eu-repo/semantics/publishedVersionca

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