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CHD-associated enhancers direct human cardiomyocyte lineage commitment.

ABSTRACT: CHD-associated enhancers direct human cardiomyocyte lineage commitment.

PROVIDER: PRJNA787259 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17170622_1.fastq.gz	Fastqsanger.gz
	SRR17170622_2.fastq.gz	Fastqsanger.gz
	SRR17170623_1.fastq.gz	Fastqsanger.gz
	SRR17170623_2.fastq.gz	Fastqsanger.gz
	SRR17170624_1.fastq.gz	Fastqsanger.gz

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CHD-associated enhancers direct human cardiomyocyte lineage commitment.

Project description:Enhancers orchestrate gene expression programs that drive multicellular development and lineage commitment. Thus, genetic variants at enhancers are thought to contribute to developmental diseases by altering cell fate commitment. However, while many variant-containing enhancers have been identified, systematic studies to endogenously test the impact of these enhancers on lineage commitment have been lacking. We performed a single-cell CRISPRi screen to directly assess the roles of 25 enhancers and putative cardiac target genes implicated in genetic studies of congenital heart defects (CHD). We identified 16 enhancers whose repression leads to delayed differentiation of human cardiomyocytes. A focused analysis on 6 TBX5 enhancers showed that TBX5 enhancer perturbation delays the transcriptional switch from mid-CM to late-CM states. Knockout of two TBX5 enhancers resulted in X and Y, which phenocopy expected CHD phenotypes. Together, these results identify critical enhancers of cardiac development and suggest that misregulation of these enhancers could contribute to cardiac defects in human patients.

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