MEF2C controls segment-specific gene regulatory networks that direct heart tube morphogenesis

Area of Science:

• Developmental Biology
• Genetics
• Molecular Biology

Background:

• Gene regulatory networks (GRNs) controlling early heart formation are partially understood.
• Lineage-specific GRNs governing cardiac development remain largely undefined.

Purpose of the Study:

• To investigate MEF2C-dependent GRNs in early heart development.
• To construct developmental trajectories and identify MEF2C-regulated enhancers.

Main Methods:

• Time-course single-nucleus RNA and ATAC sequencing in wild-type and Mef2c-null embryos.
• Deep learning-based modeling for developmental trajectory reconstruction.
• Computational identification of segment-specific enhancers.

Main Results:

• Absence of MEF2C resulted in a posteriorized cardiac gene signature and chromatin landscape.
• MEF2C-null embryos showed altered developmental trajectories for cardiac segments.
• MEF2C-dependent enhancers were identified with activity in zebrafish hearts.
• Increased NR2F2 activity was linked to Mef2c-null heart malformations.

Conclusions:

• Delineated lineage-specific GRNs in the early heart tube.
• Provided a framework for dissecting transcriptional networks in development.
• Identified NR2F2 as a key driver of Mef2c-null heart defects.