Single-cell multi-modal integrative analyses highlight functional dynamic gene regulatory networks directing human...

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Genomics

Background:

• Understanding cardiac development is crucial for addressing congenital heart disease and advancing regenerative medicine.
• Precise genetic programs guide cardiomyocyte formation, but distinct lineages and their regulators remain incompletely understood.

Purpose of the Study:

• To elucidate dynamic, cardiac-specific gene regulatory networks (GRNs) and transcriptional regulators during human cardiomyocyte development.
• To identify key factors controlling divergent cardiomyocyte lineages and their distinct gene programs.

Main Methods:

• Integration of in vitro and in vivo human single-cell multi-omic data.
• High-throughput functional genomic screening to identify critical transcription factors.
• Reconstruction of developmental trajectories from single-cell data.

Main Results:

• Discovery of divergent cardiomyocyte lineages with unique gene programs driven by specific signaling pathways.
• Identification of key transcription factors functionally regulating these distinct lineages.
• Characterization of a heat shock transcription factor 1 (HSF1)-mediated cardiometabolic GRN essential for cardiac mitochondrial function, metabolism, and survival.

Conclusions:

• Multi-modal genomic studies systematically reveal coordinated GRNs controlling distinct human cardiomyocyte populations.
• Findings provide insights into congenital heart disease mechanisms and potential cardiac regenerative therapies.
• HSF1-mediated cardiometabolic GRN is critical for fetal cardiomyocyte function and survival.