Sunday, May 25, 2025
5/25/2025
Interpreting coding/non-coding variants for congenital heart disease through gene regulatory networks - PROJECT SUMMARY Most developmental defects remain unexplained by current genetic testing. A key challenge to the prevention and treatment of congenital defects is to interpret the impact of genetic variants (especially those in non-coding regions) and to understand their molecular mechanisms of action. Our long-term goal is to understand how genetic variation contributes to congenital heart disease (CHD). We are motivated by observations that defects in cell fate commitment during development cause CHD. Numerous human and mouse genetic studies have shown that loss-of-function coding mutations in developmental transcription factors (TFs) cause CHD. Since TFs drive gene regulatory networks (GRNs), CHD variants in TFs culminate in the dysregulation of cardiac genes during development. In parallel, non-coding variants have also been linked to CHD. Many of these variants are thought to modify the activity of transcriptional enhancers, especially those that control the expression of developmental TFs and regulatory programs. Together, these studies motivate the need to interpret variant function in the context of developmental regulatory networks. The objective of this proposal is to use cardiac regulatory networks as a platform to understand CHD genes and variants (Figure 1). We will define cardiac development networks (enhancer → TF → genes) and use this network to interpret the functions of coding TF variants and non-coding enhancer variants (both patient-derived and those not yet observed). We hypothesize that this systematic dissection of cardiac GRNs will enable the characterization of variants that impact cardiomyocyte (CM) specification and contribute to CHD. Our rationale is that this knowledge will help define the missing heritability of congenital abnormalities. We propose the following specific aims: (Aim 1) Define the transcription factors and gene regulatory networks of human cardiac development; (Aim 2) Define and characterize genetic variants regulating cardiac gene programs; (Aim 3) Characterize the impact of coding/non- coding variants on molecular and cellular phenotypes. This proposal is innovative because it will use experimentally-derived gene regulatory networks as a platform to interpret CHD genes and coding/non-coding variants. We expect this resource to propel new research horizons. This proposal is significant because it will expand our understanding of how genetic variants impact TF activity, the state of cardiac gene regulatory networks, and lineage specification, which will enable the functional interpretation of known and novel variants in CHD patients.
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