CHD-associated enhancers shape human cardiomyocyte lineage commitment

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,...

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Published in:eLife 2023-04, Vol.12
Main Authors: Armendariz, Daniel A, Goetsch, Sean C, Sundarrajan, Anjana, Sivakumar, Sushama, Wang, Yihan, Xie, Shiqi, Munshi, Nikhil V, Hon, Gary C
Format: Article
Language:English
Subjects:
cardiomyocyte
Cardiomyocytes
Cell Differentiation - genetics
Cell fate
congenital heart disease
CRISPR
Developmental disabilities
Enhancers
Epigenetics
Gene expression
gene regulation
Genes
Genetic diversity
genetic variation
Genetics and Genomics
Genomes
Heart
Heart Defects, Congenital - genetics
Humans
Myocytes, Cardiac - metabolism
Regulatory Sequences, Nucleic Acid
single cell
Stem cells
Stem Cells and Regenerative Medicine
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Summary: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, studies to endogenously test the impact of these enhancers on lineage commitment have been lacking. We perform a single-cell CRISPRi screen to assess the endogenous roles of 25 enhancers and putative cardiac target genes implicated in genetic studies of congenital heart defects (CHDs). We identify 16 enhancers whose repression leads to deficient differentiation of human cardiomyocytes (CMs). A focused CRISPRi validation screen shows that repression of TBX5 enhancers delays the transcriptional switch from mid- to late-stage CM states. Endogenous genetic deletions of two TBX5 enhancers phenocopy epigenetic perturbations. Together, these results identify critical enhancers of cardiac development and suggest that misregulation of these enhancers could contribute to cardiac defects in human patients.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.86206