National Heart, Lung, and Blood Institute 5U01HL157989-05

Genetic determinants of 4D genome folding in human cardiac development

This NIH-funded project aims to understand how 3D genome folding regulates human cardiac development and how mutations causing congenital heart disease affect this process, using iPS cell models and machine learning.

Description

A major unanswered question is how chromatin topology coordinates human development and cellular differentiation, and how genome folding is differentially regulated in human disease. It is thought that three-dimensional (3D) chromatin organization is driven by transcriptional regulators, but fundamental mechanisms of this regulation as it relates to disease-relevant human cells have not been well explored. We propose to elucidate the temporally dynamic 3D nucleome (4DN) that underlies human cardiac differentiation, its molecular underpinnings, and the impact of mutations that underlie defective 4DN organization in human congenital heart disease (CHD). CHDs are the most common birth defect and arise from abnormal heart development. The genetic basis of CHD is largely mutations in genes encoding chromatin modifiers (e.g., WDR5, KMT2D) and transcription factors (e.g., TBX5, GATA4), many of which also cause adult-onset arrhythmias. The impact of CHD mutations on the 4DN has not been explored. We hypothesize that 3D genome folding is highly regulated during cardiac differentiation and is impacted by disease-causing mutations in transcriptional regulators and non-coding elements. We will use iPS cell models and machine learning to elucidate dynamic 3D chromatin organization in human cardiomyocytes and endothelial cells during normal and diseased cardiac differentiation.

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