期刊
DEVELOPMENTAL CELL
卷 56, 期 3, 页码 292-+出版社
CELL PRESS
DOI: 10.1016/j.devcel.2020.11.020
关键词
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资金
- National Institutes of Health [UM1HL098179, UM1HL098166, R01HL114948, USCF CVRI 2T32HL007731-27]
- California Institute for Regenerative Medicine [RB4-05901]
- Office of the Assistant Secretary of Defense for Health Affairs [W81XWH-17-1-0191]
- Foundation for Anesthesia Education and Research (Mentored Research Training Grant)
- Society for Pediatric Anesthesia (Young Investigator Award)
- Hellman Family Fund
- UCSF REAC
- UCSF Department of Anesthesia and Perioperative Care (New Investigator Award)
- Spanish Institute of Health Carlos III (ISCIII) [CP14/00229]
- Ministerio de Ciencia, Innovacion y Universidades (AEI/FEDER, UE) [SAF2017-89109-P]
- NIH/NCRR grant [C06 RR018928]
- NHGRI [5U41HG002371]
- CIRM [GC1R-06673-C]
- Silicon Valley Community Foundation [2018-182809]
- Younger Family Fund
Lower dosage of the CHD transcription factor TBX5 results in highly sensitive dysregulation in discrete subsets of iPSC-derived cardiomyocytes, affecting pathways related to heart development, cardiomyocyte function, and CHD genetics, and potentially leading to the occurrence of congenital heart diseases.
Haploinsufficiency of transcriptional regulators causes human congenital heart disease (CHD); however, the underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define transcriptional consequences of reduced dosage of the CHD transcription factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways-including lineage decisions and genes associated with heart development, cardiomyocyte function, and CHD genetics-in discrete subpopulations of cardiomyocytes. Spatial transcriptomic mapping revealed chamber-restricted expression for many TBX5-sensitive transcripts. GRN analysis indicated that cardiac network stability, including vulnerable CHD-linked nodes, is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between Tbx5 and Mef2c, manifesting as ventricular septation defects, was validated in mice. These results demonstrate exquisite and diverse sensitivity to TBX5 dosage in heterogeneous subsets of iPSC-derived cardiomyocytes and predicts candidate GRNs for human CHDs, with implications for quantitative transcriptional regulation in disease.
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