CTCF counter-regulates cardiomyocyte development and maturation programs in the embryonic heart [RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE77588 | GEO | 2017/08/21
SECONDARY ACCESSION(S): PRJNA311076
REPOSITORIES: GEO
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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.
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Project description:Understanding the principles of endogenous chromatin structure has key implications for epigenetic therapy. To determine the mechanisms of genome structure-function in post-mitotic cells, genome-wide chromatin conformation capture was performed in cardiac myocytes, a non-dividing, differentiated cell responsible for cardiac contraction. Cardiac-specific CTCF knockout mice demonstrated that loss of CTCF had minimal effect on topologically associating domains; however, it selectively altered boundary strength and A/B compartmentalization, with gene expression changes mimicking those in heart failure. Loss of CTCF (or subjecting wild-type mice to clinically relevant pressure overload stress) remodeled long-range chromatin looping to alter 3D proximity of enhancers and disease causing genes. Depletion of CTCF was sufficient to induce heart failure in mice and human heart failure patients receiving mechanical unloading to attenuate disease progression show increased CTCF expression. These findings establish CTCF in the maintenance of chromatin looping and identify global chromatin remodeling as a causative factor in heart failure.
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Project description:Understanding the principles of endogenous chromatin structure has key implications for epigenetic therapy. To determine the mechanisms of genome structure-function in post-mitotic cells, genome-wide chromatin conformation capture was performed in cardiac myocytes, a non-dividing, differentiated cell responsible for cardiac contraction. Cardiac-specific CTCF knockout mice demonstrated that loss of CTCF had minimal effect on topologically associating domains; however, it selectively altered boundary strength and A/B compartmentalization, with gene expression changes mimicking those in heart failure. Loss of CTCF (or subjecting wild-type mice to clinically relevant pressure overload stress) remodeled long-range chromatin looping to alter 3D proximity of enhancers and disease causing genes. Depletion of CTCF was sufficient to induce heart failure in mice and human heart failure patients receiving mechanical unloading to attenuate disease progression show increased CTCF expression. These findings establish CTCF in the maintenance of chromatin looping and identify global chromatin remodeling as a causative factor in heart failure.
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