Organ-specific regulatory logic orchestrates gene expression in the coelomic mesothelium

The embryonic (coelomic) mesothelium undergoes epithelial-to-mesenchymal transition (EMT) to promote vascular growth and parenchymal development. A prominent example is the epicardium, which plays an essential role during heart development. Little is known about the mechanisms behind gene regulation in the coelomic mesothelium, and organ-specific enhancer logic that endows specialization. Using gene regulatory network inference via single-cell multi-omics, our study reveals trans- and cis-regulatory elements (CREs) that regulate mesothelial gene expression in three organs: heart, lung, and pancreas. Here, we expand on pivotal transcription factors (TFs) and CREs specific to the epicardium. In contrast, we find that the TF MAF may orchestrate pan-mesothelial gene expression via conserved CREs, which are absent from non-mesothelial lineages. MAF may preserve mesothelial identity, evidenced by negative correlation with EMT and conservation in mouse and human epicardial cells. Collectively, our work sheds light on the regulatory logic behind cell type identity and leverages single-cell integration to gain insights into mammalian organ development.