Organ-specific and conserved regulatory logic orchestrates gene expression in the embryonic mesothelium

Summary 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, or the organ-specific enhancer logic that endows specialization. Using gene regulatory network inference via multi-omic analysis, our study reveals trans - and cis -regulatory elements (CREs) that regulate mesothelial gene expression in three organs: heart, lung, and pancreas. We delineate pivotal transcription factors (TFs) and CREs specific to the epicardium, and show, in contrast, that the TF MAF orchestrates pan-mesothelial gene expression via conserved CREs, which are absent in non-mesothelial lineages. MAF may preserve mesothelial identity, evidenced by negative correlation with EMT and mouse-human conservation. Collectively, our work elucidates the regulatory logic behind cell type identity and leverages single-cell integration to gain insights into mammalian organ development. Highlights Coelomic mesothelia display distinct transcriptome linked to their morphogenic role Mesothelial markers associate with organ-specific trans- and cis- regulatory logic Pan-mesothelial gene regulatory mechanisms control canonical marker expression Integrating mouse and human datasets uncovers conserved dynamics of epicardial EMT