Gao, XinWu, TongyuJohnson, Kirby D.Lahvic, Jamie L.Ranheim, Erik A.Zon, Leonard I.Bresnick, Emery H.2016-04-012016Gao, Xin, Tongyu Wu, Kirby D. Johnson, Jamie L. Lahvic, Erik A. Ranheim, Leonard I. Zon, and Emery H. Bresnick. 2016. “GATA Factor-G-Protein-Coupled Receptor Circuit Suppresses Hematopoiesis.” Stem Cell Reports 6 (3): 368-382. doi:10.1016/j.stemcr.2016.01.008. http://dx.doi.org/10.1016/j.stemcr.2016.01.008.2213-6711http://nrs.harvard.edu/urn-3:HUL.InstRepos:26318585Summary Hematopoietic stem cells (HSCs) originate from hemogenic endothelium within the aorta-gonad-mesonephros (AGM) region of the mammalian embryo. The relationship between genetic circuits controlling stem cell genesis and multi-potency is not understood. A Gata2 cis element (+9.5) enhances Gata2 expression in the AGM and induces the endothelial to HSC transition. We demonstrated that GATA-2 rescued hematopoiesis in +9.5−/− AGMs. As G-protein-coupled receptors (GPCRs) are the most common targets for FDA-approved drugs, we analyzed the GPCR gene ensemble to identify GATA-2-regulated GPCRs. Of the 20 GATA-2-activated GPCR genes, four were GATA-1-activated, and only Gpr65 expression resembled Gata2. Contrasting with the paradigm in which GATA-2-activated genes promote hematopoietic stem and progenitor cell genesis/function, our mouse and zebrafish studies indicated that GPR65 suppressed hematopoiesis. GPR65 established repressive chromatin at the +9.5 site, restricted occupancy by the activator Scl/TAL1, and repressed Gata2 transcription. Thus, a Gata2 cis element creates a GATA-2-GPCR circuit that limits positive regulators that promote hematopoiesis.en-USJournal Article2016-04-0110.1016/j.stemcr.2016.01.008