title: GATA Factor-G-Protein-Coupled Receptor Circuit Suppresses Hematopoiesis.
abstract: 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.
authors.affiliation: UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Tongyu
authors.initials: T
authors.lastname: Wu
authors.affiliation: UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Kirby D
authors.initials: KD
authors.lastname: Johnson
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA 02114, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Lahvic
authors.affiliation: Department of Pathology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Ranheim
authors.affiliation: Stem Cell Program and Division of Hematology/Oncology, Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA 02114, USA.
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.affiliation: UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. Electronic address: ehbresni@wisc.edu.
authors.forename: Emery H
authors.initials: EH
authors.lastname: Bresnick
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D002843:Chromatin; D050989:GATA2 Transcription Factor; D043562:Receptors, G-Protein-Coupled