Transcriptional regulation of Hhex in hematopoiesis and hematopoietic stem cell ontogeny.

摘要: Hematopoietic stem cells (HSCs) emerge during development via an endothelial-to-hematopoietic transition from hemogenic endothelium of the dorsal aorta (DA). Using in situ hybridization and analysis a knock-in RedStar reporter, we show that transcriptional regulator Hhex is expressed (DA) clusters putative HSCs as they are specified murine development. We exploited this observation, using locus to define cis regulatory elements, enhancers interacting transcription factors both necessary sufficient support gene expression emerging HSC. identify evolutionarily conserved non-coding region (ECR) with capacity bind hematopoietic-affiliated regulators Gata2, SCL, Fli1, Pu.1 Ets1/2. This drive transgenic GFP reporter DA intra-aortic hematopoietic clusters. GFP-positive AGM co-expressed HSC-associated markers c-Kit, CD34, VE-Cadherin, CD45, were capable multipotential differentiation long term engraftment when transplanted into myelo-ablated recipients. The ECR was also at additional blood sites including yolk sac islands, fetal liver, vitelline umbilical arteries adult bone marrow, suggesting common mechanism for regulation throughout ontogenesis system. To explore physiological requirement hematoendothelial development, deleted element endogenous context targeted Hhex-RedStar allele. Results indicate specific blood-associated further demonstrate HSC compartment. Taken together, our results identified enhancer homeostasis. thus appears be core node convergence factor network governs emergence HSCs.