PT - JOURNAL ARTICLE AU - Irfan S. Kathiriya AU - Kavitha S. Rao AU - Giovanni Iacono AU - W. Patrick Devine AU - Andrew P. Blair AU - Swetansu K. Hota AU - Michael H. Lai AU - Bayardo I. Garay AU - Reuben Thomas AU - Henry Z. Gong AU - Lauren K. Wasson AU - Piyush Goyal AU - Tatyana Sukonnik AU - Gunes A. Akgun AU - Laure D. Bernard AU - Brynn N. Akerberg AU - Fei Gu AU - Kai Li AU - William T. Pu AU - Joshua M. Stuart AU - Christine E. Seidman AU - J. G. Seidman AU - Holger Heyn AU - Benoit G. Bruneau TI - Modeling human <em>TBX5</em> haploinsufficiency predicts regulatory networks for congenital heart disease AID - 10.1101/835603 DP - 2020 Jan 01 TA - bioRxiv PG - 835603 4099 - http://biorxiv.org/content/early/2020/05/21/835603.short 4100 - http://biorxiv.org/content/early/2020/05/21/835603.full AB - 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 between Tbx5 and Mef2c was 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.Competing Interest StatementB.G.B. is a co-founder and shareholder of Tenaya Therapeutics. None of the work presented here is related to the interests of Tenaya Therapeutics.