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Abstract
The mesothelium is a protective barrier on the outmost layer of coelomic organs and plays an essential role in organ development, especially during heart development. Only with the presence of mesothelium over the heart, also known as epicardium, coronary blood vessels start to form to support blood supply to the heart. Epicardium can also secrete paracrine factors to facilitate cardiomyocytes maturation and blood vessel formation. However, little is known about molecular mechanisms in the mesothelium/epicardium specification. Therefore, in this project, we aim at utilizing high throughput sequencing techniques (RNA-seq and ATAC-seq) along with CRISPR-Cas9 knockout technique on an in vitro human pluripotent stem cell (hPSC) based mesothelium differentiation model to identify and investigate a key transcription network involved in human mesothelium development. Our study identified that GATA4 was the essential pioneer factor in driving mesothelium specification and GATA4 cannot be replaced by GATA6 in mesothelium determination. We also discovered that the specificity of GATA4 in mesothelium depends on its interaction with TBX5 at codon 296 of human GATA4. The role of GATA4 and TBX5 in mesothelium formation is conserved in mouse and human.