Single Ventricle Etiology: Phenotype-Genotype Relationship & Model System Development


Ets1 in hypoplastic left heart syndrome

Shuyi Nie, Ph.D, Georgia Institute of Technology

Award Type: Innovation Fund

Abstract: Hypoplastic left heart syndrome (HLHS) is the most common cause of death in infants with congenital heart defects. Although it is clearly a genetic disease, little is known about the genetic mechanisms and pathophysiology underlying HLHS. In human, Ets1 has been identified as the genetic cause for heart defects in Jacobson Syndrome, in which HLHS is highly overrepresented. However, in mouse, loss of Ets1 leads to a series of heart defects including ventricular septal defects, non-compaction of left ventricle, and double-outlet right ventricle depending on the genetic backgrounds, but rarely HLHS. Recently, we showed that in frog, Ets1 loss leads to a heart phenotype very similar to that of human HLHS heart. The ventricular wall is thicker with a loss of ventricular trabeculation and a greatly reduced chamber size. There is also a subset of embryos with a growth arrested ventricle, suggesting that the development of HLHS-like phenotype may be a multi-step process. Using this model, we further demonstrated that Ets1 is particularly required in the cardiac mesoderm, rather than the cardiac neural crest cells for the heart development, consistent with an aortic arch artery contribution of the frog cardiac neural crest cells. Our ongoing work also indicates that the development of endocardium is impaired at Ets1 knocked down, suggesting that HLHS may result from a disrupted endocardium to myocardium signaling.

Modeling human TBX5 haploinsufficiency predicts regulatory networks for congenital heart disease:

Dr Irfan Kathiriya MD, PhD, University of California, San Francisco/Gladstone Institutes

Award Type:  Innovation Fund (Benoit Bruneau)

Abstract: 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 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 betweenTbx5 and Mef2c was validated in mouse, manifesting as ventricular septation defects. 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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