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CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart

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dc.contributor.authorGomez-Velazquez, Melisa
dc.contributor.authorBadia-Careaga, Claudio
dc.contributor.authorLechuga-Vieco, Ana V.
dc.contributor.authorNieto-Arellano, Rocio
dc.contributor.authorTena, Juan J.
dc.contributor.authorRollan, Isabel
dc.contributor.authorAlvarez, Alba
dc.contributor.authorTorroja, Carlos
dc.contributor.authorCaceres, Eva F.
dc.contributor.authorRoy, Anna
dc.contributor.authorGaljart, Niels
dc.contributor.authorDelgado-Olguin, Paul
dc.contributor.authorSanchez-Cabo, Fatima
dc.contributor.authorEnriquez, Jose Antonio
dc.contributor.authorLuis Gomez-Skarmeta, Jose
dc.contributor.authorManzanares, Miguel
dc.contributor.funderMinisterio de Economía y Competitividad (España)
dc.contributor.funderComunidad de Madrid (España)
dc.contributor.funderRegional Government of Andalusia (España)
dc.contributor.funderPablo de Olavide University (España)
dc.contributor.funderHeart and Stroke Foundation (Canadá)
dc.contributor.funderOperational Funds from the Hospital for Sick Children
dc.contributor.funderNatural Sciences and Engineering Research Council (Canada)
dc.contributor.funderCanadian Institutes of Health Research
dc.contributor.funderFundación ProCNIC
dc.contributor.funderMinisterio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
dc.date.accessioned2017-10-20T10:23:10Z
dc.date.available2017-10-20T10:23:10Z
dc.date.issued2017
dc.description.abstractCardiac progenitors are specified early in development and progressively differentiate and mature into fully functional cardiomyocytes. This process is controlled by an extensively studied transcriptional program. However, the regulatory events coordinating the progression of such program from development to maturation are largely unknown. Here, we show that the genome organizer CTCF is essential for cardiogenesis and that it mediates genomic interactions to coordinate cardiomyocyte differentiation and maturation in the developing heart. Inactivation of Ctcf in cardiac progenitor cells and their derivatives in vivo during development caused severe cardiac defects and death at embryonic day 12.5. Genome wide expression analysis in Ctcf mutant hearts revealed that genes controlling mitochondrial function and protein production, required for cardiomyocyte maturation, were upregulated. However, mitochondria from mutant cardiomyocytes do not mature properly. In contrast, multiple development regulatory genes near predicted heart enhancers, including genes in the IrxA cluster, were downregulated in Ctcf mutants, suggesting that CTCF promotes cardiomyocyte differentiation by facilitating enhancer-promoter interactions. Accordingly, loss of CTCF disrupts gene expression and chromatin interactions as shown by chromatin conformation capture followed by deep sequencing. Furthermore, CRISPR-mediated deletion of an intergenic CTCF site within the IrxA cluster alters gene expression in the developing heart. Thus, CTCF mediates local regulatory interactions to coordinate transcriptional programs controlling transitions in morphology and function during heart development.
dc.description.peerreviewedSí
dc.description.sponsorshipThis work was funded by the Spanish Ministerio de Economia y Competitividad (grants BFU2011-23083 and BFU2014-54608-P to MM, BFU2013-41322-P to JLGS and BFU2014-58449-JIN to JJT), the Comunidad Autonoma de Madrid (grant CELLDD-CM to MM), the Andalusian regional government (grant BIO-396 to JLGS), the Universidad Pablo de Olavide (postdoctoral grant to JJT). PDO is funded by the Heart and Stroke Foundation of Canada (G-17-0018613), Operational Funds from the Hospital for Sick Children, the Natural Sciences and Engineering Research Council of Canada (NSERC) (500865 to PDO), and the Canadian Institutes of Health Research (CIHR) (PJT-149046). The CNIC is supported by the Spanish Ministerio de Economia y Competitividad and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
dc.format.volume13
dc.identifierISI:000408763800046
dc.identifier.citationPLoS Genet. 2017; 13(8):e1006985
dc.identifier.doi10.1371/journal.pgen.1006985
dc.identifier.issn1553-7404
dc.identifier.journalPlos Genetics
dc.identifier.pubmedID28846746
dc.identifier.urihttp://hdl.handle.net/20.500.12105/5102
dc.language.isoeng
dc.publisherPublic Library of Science (PLOS)
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2011-23083es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2014-54608-Pes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2013-41322-Pes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BFU2014-58449-JINes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SEV-2015-0505es_ES
dc.relation.publisherversionhttps://doi.org/10.1371/journal.pgen.1006985
dc.repisalud.institucionCNIC
dc.repisalud.orgCNICCNIC::Grupos de investigación::Genética Funcional del Sistema de Fosforilación Oxidativa
dc.repisalud.orgCNICCNIC::Unidades técnicas::Bioinformática
dc.rights.accessRightsopen accesses_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectGENE-EXPRESSION
dc.subjectTRANSCRIPTION FACTORS
dc.subjectNEURAL DEVELOPMENT
dc.subjectDNA INTERACTIONS
dc.subjectHUMAN GENOME
dc.subjectHUMAN-CELLS
dc.subjectMITOCHONDRIAL
dc.subjectORGANIZATION
dc.subjectMAP
dc.subjectDIFFERENTIATION
dc.titleCTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart
dc.typejournal article
dc.type.hasVersionVoR
dspace.entity.typePublication
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