Modeling Human TBX5 Haploinsufficiency Predicts Regulatory Networks for Congenital Heart Disease.
IF: 13.417
Cited by: 51


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.


Spatial Transcriptomics
cardiomyocyte differentiation
congenital heart disease
disease modeling
gene dosage
gene regulation
gene regulatory networks
human induced pluripotent stem cells
single cell transcriptomics
transcription factor

MeSH terms

Body Patterning
Cell Differentiation
Gene Dosage
Gene Regulatory Networks
Heart Defects, Congenital
Heart Ventricles
MEF2 Transcription Factors
Models, Biological
Myocytes, Cardiac
T-Box Domain Proteins
Transcription, Genetic


Kathiriya, Irfan S
Rao, Kavitha S
Iacono, Giovanni
Devine, W Patrick
Blair, Andrew P
Hota, Swetansu K
Lai, Michael H
Garay, Bayardo I
Thomas, Reuben
Gong, Henry Z
Wasson, Lauren K
Goyal, Piyush
Sukonnik, Tatyana
Hu, Kevin M
Akgun, Gunes A
Bernard, Laure D
Akerberg, Brynn N
Gu, Fei
Li, Kai
Speir, Matthew L
Haeussler, Maximilian
Pu, William T
Stuart, Joshua M
Seidman, Christine E
Seidman, J G
Heyn, Holger
Bruneau, Benoit G

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