CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE77644 | GEO | 2017/08/21
SECONDARY ACCESSION(S): PRJNA311079
REPOSITORIES: GEO
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Project 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.
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Project description:Analysis of chromatin architecture suggests that the 3D structure of the genome plays a major role in regulating gene expression, orchestrating the compartmentalization of chromatin and facilitating specific enhancer-promoter interactions. However, the mechanisms that control this structuring of the genome are not fully understood. We have addressed this issue by analyzing the role of CTCF, a major architectural factor in chromatin structure, in the embryonic heart. Loss of CTCF triggered an overall downregulation of the cardiac developmental program, suggesting that CTCF facilitates enhancer-promoter interactions in the developing heart. Detailed analysis of the IrxA gene cluster showed that CTCF loss leads to disruption of the heart-specific regulatory domain that surrounds Irx4, resulting in changes in expression of IrxA cluster genes and neighboring genes. In contrast to the critical role proposed for CTCF in organizing large-scale chromatin domains, our results show that CTCF preferentially mediates local regulatory interactions.
2017-08-21 | GSE99118 | GEO
Project description:Analysis of chromatin architecture suggests that the 3D structure of the genome plays a major role in regulating gene expression, orchestrating the compartmentalization of chromatin and facilitating specific enhancer-promoter interactions. However, the mechanisms that control this structuring of the genome are not fully understood. We have addressed this issue by analyzing the role of CTCF, a major architectural factor in chromatin structure, in the embryonic heart. Loss of CTCF triggered an overall downregulation of the cardiac developmental program, suggesting that CTCF facilitates enhancer-promoter interactions in the developing heart. Detailed analysis of the IrxA gene cluster showed that CTCF loss leads to disruption of the heart-specific regulatory domain that surrounds Irx4, resulting in changes in expression of IrxA cluster genes and neighboring genes. In contrast to the critical role proposed for CTCF in organizing large-scale chromatin domains, our results show that CTCF preferentially mediates local regulatory interactions.
2017-08-21 | GSE77588 | GEO
Project description:CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart
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Project description:This SuperSeries is composed of the SubSeries listed below.
2023-03-17 | GSE201027 | GEO