title: Chromatin-wide and transcriptome profiling integration uncovers p38α MAPK as a global regulator of skeletal muscle differentiation.
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.
authors.affiliation: Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative diseases (CIBERNED), Barcelona, Spain.
authors.forename: Jessica
authors.initials: J
authors.lastname: Segalés
authors.affiliation: Department of Genetic Engineering and Biotechnology, University of Dhaka, Dhaka, 1000 Bangladesh.
authors.forename: Abul B M M K
authors.initials: AB
authors.lastname: Islam
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115 USA.
authors.forename: Roshan
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6 Canada.
authors.forename: Qi-Cai
authors.initials: QC
authors.lastname: Liu
authors.affiliation: Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative diseases (CIBERNED), Barcelona, Spain ; Present address: Buck Institute for Research on Aging, Novato, CA USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Sousa-Victor
authors.affiliation: Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6 Canada.
authors.forename: F Jeffrey
authors.initials: FJ
authors.lastname: Dilworth
authors.affiliation: Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
authors.affiliation: Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative diseases (CIBERNED), Barcelona, Spain.
authors.forename: Eusebio
authors.initials: E
authors.lastname: Perdiguero
authors.affiliation: Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative diseases (CIBERNED), Barcelona, Spain ; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Pura
authors.initials: P
authors.lastname: Muñoz-Cánoves
mesh_terms: D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D005838:Genotype; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D024510:Muscle Development / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects / Q000201:enzymology*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14