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CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart
Cardiac 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 devel...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591014/ https://www.ncbi.nlm.nih.gov/pubmed/28846746 http://dx.doi.org/10.1371/journal.pgen.1006985 |
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author | Gomez-Velazquez, Melisa Badia-Careaga, Claudio Lechuga-Vieco, Ana Victoria Nieto-Arellano, Rocio Tena, Juan J. Rollan, Isabel Alvarez, Alba Torroja, Carlos Caceres, Eva F. Roy, Anna R. Galjart, Niels Delgado-Olguin, Paul Sanchez-Cabo, Fatima Enriquez, Jose Antonio Gomez-Skarmeta, Jose Luis Manzanares, Miguel |
author_facet | Gomez-Velazquez, Melisa Badia-Careaga, Claudio Lechuga-Vieco, Ana Victoria Nieto-Arellano, Rocio Tena, Juan J. Rollan, Isabel Alvarez, Alba Torroja, Carlos Caceres, Eva F. Roy, Anna R. Galjart, Niels Delgado-Olguin, Paul Sanchez-Cabo, Fatima Enriquez, Jose Antonio Gomez-Skarmeta, Jose Luis Manzanares, Miguel |
author_sort | Gomez-Velazquez, Melisa |
collection | PubMed |
description | Cardiac 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. |
format | Online Article Text |
id | pubmed-5591014 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-55910142017-09-15 CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart Gomez-Velazquez, Melisa Badia-Careaga, Claudio Lechuga-Vieco, Ana Victoria Nieto-Arellano, Rocio Tena, Juan J. Rollan, Isabel Alvarez, Alba Torroja, Carlos Caceres, Eva F. Roy, Anna R. Galjart, Niels Delgado-Olguin, Paul Sanchez-Cabo, Fatima Enriquez, Jose Antonio Gomez-Skarmeta, Jose Luis Manzanares, Miguel PLoS Genet Research Article Cardiac 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. Public Library of Science 2017-08-28 /pmc/articles/PMC5591014/ /pubmed/28846746 http://dx.doi.org/10.1371/journal.pgen.1006985 Text en © 2017 Gomez-Velazquez et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Gomez-Velazquez, Melisa Badia-Careaga, Claudio Lechuga-Vieco, Ana Victoria Nieto-Arellano, Rocio Tena, Juan J. Rollan, Isabel Alvarez, Alba Torroja, Carlos Caceres, Eva F. Roy, Anna R. Galjart, Niels Delgado-Olguin, Paul Sanchez-Cabo, Fatima Enriquez, Jose Antonio Gomez-Skarmeta, Jose Luis Manzanares, Miguel CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart |
title | CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart |
title_full | CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart |
title_fullStr | CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart |
title_full_unstemmed | CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart |
title_short | CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart |
title_sort | ctcf counter-regulates cardiomyocyte development and maturation programs in the embryonic heart |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591014/ https://www.ncbi.nlm.nih.gov/pubmed/28846746 http://dx.doi.org/10.1371/journal.pgen.1006985 |
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