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

The gene regulatory networks (GRNs) that control early heart formation are beginning to be understood, but lineage-specific GRNs remain largely undefined. We investigated networks controlled by the vital transcription factor MEF2C using a time course of single-nucleus RNA sequencing and ATAC sequencing in wild-type and <i>Mef2c</i>-null embryos. We identified a "posteriorized" cardiac gene signature and chromatin landscape in the absence of MEF2C. Integrating our multiomics data in a deep learning-based model, we constructed developmental trajectories for each of the outflow tract, ventricular, and inflow tract segments and alterations of these in <i>Mef2c</i>-null embryos. We computationally identified segment-specific MEF2C-dependent enhancers with activity in the developing zebrafish heart. Finally, using inferred GRNs, we discovered that the <i>Mef2c</i>-null heart malformations are partly driven by increased activity of the nuclear hormone receptor NR2F2. Our results delineate lineage-specific GRNs in the early heart tube and provide a generalizable framework for dissecting transcriptional networks governing developmental processes.