1. Modeling Human TBX5 Haploinsufficiency Predicts Regulatory Networks for Congenital Heart Disease
- Author
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Tatyana Sukonnik, Fei Gu, Maximilian Haeussler, W. Patrick Devine, Reuben Thomas, Kavitha S. Rao, Michael H. Lai, Matthew L. Speir, William T. Pu, Irfan S. Kathiriya, Piyush Goyal, Bayardo I. Garay, Jonathan G. Seidman, Kai Li, Swetansu K. Hota, Andrew Blair, Benoit G. Bruneau, Henry Gong, Laure D. Bernard, Gunes A. Akgun, Holger Heyn, Lauren K. Wasson, Joshua M. Stuart, Giovanni Iacono, Kevin M. Hu, Brynn N. Akerberg, and Christine E. Seidman
- Subjects
Transcription, Genetic ,Gene Dosage ,Gene regulatory network ,Haploinsufficiency ,single cell transcriptomics ,Cardiovascular ,Medical and Health Sciences ,Congenital ,Mice ,0302 clinical medicine ,Models ,disease modeling ,Transcriptional regulation ,2.1 Biological and endogenous factors ,Gene Regulatory Networks ,Myocytes, Cardiac ,MEF2C ,Aetiology ,Induced pluripotent stem cell ,transcription factor ,Heart Defects ,Pediatric ,Regulation of gene expression ,0303 health sciences ,Heart development ,MEF2 Transcription Factors ,Cell Differentiation ,Biological Sciences ,cardiomyocyte differentiation ,congenital heart disease ,Heart Disease ,Cardiac ,Transcription ,Heart Defects, Congenital ,1.1 Normal biological development and functioning ,Heart Ventricles ,Computational biology ,Biology ,Models, Biological ,Gene dosage ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Genetic ,Underpinning research ,Genetics ,Animals ,Humans ,Molecular Biology ,Heart Disease - Coronary Heart Disease ,Body Patterning ,030304 developmental biology ,Myocytes ,Human Genome ,Cell Biology ,Biological ,Stem Cell Research ,human induced pluripotent stem cells ,Mutation ,Congenital Structural Anomalies ,gene regulation ,T-Box Domain Proteins ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
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.
- Published
- 2021
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