Modeling humanTBX5haploinsufficiency predicts regulatory networks for congenital heart disease
| Autor: | Reuben Thomas, Giovanni Iacono, Fei Gu, W. Patrick Devine, Tatyana Sukonnik, Bayardo I. Garay, Christine E. Seidman, Jonathan G. Seidman, Kai Li, Kavitha S. Rao, Benoit G. Bruneau, Henry Gong, Swetansu K. Hota, Irfan S. Kathiriya, William T. Pu, Andrew Blair, Piyush Goyal, Brynn N. Akerberg, Lauren K. Wasson, Laure D. Bernard, Gunes A. Akgun, Michael H. Lai, Holger Heyn, Joshua M. Stuart |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Heart disease Gene regulatory network Biology medicine.disease Cell biology 03 medical and health sciences 0302 clinical medicine 030220 oncology & carcinogenesis Transcriptional regulation medicine MEF2C Induced pluripotent stem cell Haploinsufficiency Gene Transcription factor 030304 developmental biology |
| DOI: | 10.1101/835603 |
| Popis: | Haploinsufficiency of transcriptional regulators causes human congenital heart disease (CHD). However, underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define transcriptional consequences of reduced dosage of the CHD-linked 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 cardiomyocyte function and CHD genetics—in discrete subpopulations of cardiomyocytes. GRN analysis identified vulnerable nodes enriched for CHD genes, indicating that cardiac network stability is sensitive to TBX5 dosage. A GRN-predicted genetic interaction betweenTbx5andMef2cwas validated in mouse, manifesting as ventricular septation defects. These results demonstrate exquisite sensitivity to TBX5 dosage by diverse transcriptional responses in heterogeneous subsets of iPSC-derived cardiomyocytes. This predicts candidate GRNs for human CHDs, with implications for quantitative transcriptional regulation in disease. |
| Databáze: | OpenAIRE |
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