PUBLICATION

GATA Factor-G-Protein-Coupled Receptor Circuit Suppresses Hematopoiesis

Authors
Gao, X., Wu, T., Johnson, K.D., Lahvic, J.L., Ranheim, E.A., Zon, L.I., Bresnick, E.H.
ID
ZDB-PUB-160226-22
Date
2016
Source
Stem Cell Reports   6(3): 368-82 (Journal)
Registered Authors
Zon, Leonard I.
Keywords
none
MeSH Terms
  • Animals
  • Cells, Cultured
  • Chromatin/genetics
  • Chromatin/metabolism
  • GATA2 Transcription Factor/genetics
  • GATA2 Transcription Factor/metabolism*
  • Hematopoiesis*
  • Hematopoietic Stem Cells/cytology*
  • Hematopoietic Stem Cells/metabolism
  • Mice
  • Receptors, G-Protein-Coupled/metabolism*
  • Zebrafish
PubMed
26905203 Full text @ Stem Cell Reports
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.
Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping