DNA methyltransferase Dnmt3ba-mediated epigenetic modulation of Integrin signaling is essential for hematopoietic...

In vertebrate embryonic development, hematopoietic stem and progenitor cells (HSPCs) originate from a subset of arterial endothelial cells in the ventral wall of the dorsal aorta through endothelial-to-hematopoietic transition (EHT). Despite extensive research efforts, gaps persist in understanding the establishment of HSPC development. In this study, we demonstrate that DNA methyltransferase 3ba (Dnmt3ba), highly expressed in the hemogenic endothelial cells (HECs), plays a crucial role in regulating HEC survival in zebrafish. Dnmt3ba deficiency leads to hypomethylation at the itgα3b and itgα7 loci, diminishing the expression of these Integrins and downstream Akt signaling and Mdm2 phosphorylation, while concurrently triggering HEC apoptosis by upregulation of P53 activity. Manipulation of DNMT3B in an iPSC-derived human hematopoietic differentiation system indicates functional conservation. Collectively, our findings unveil an epigenetic mechanism governed by Dnmt3ba, orchestrating HEC survival through epigenetic modulation of Integrin signaling.