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

Stem Cell Reports
Xin GaoEmery H Bresnick

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.

References

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Citations

Feb 10, 2017·Blood·Koichi R KatsumuraUNKNOWN GATA Factor Mechanisms Group
May 24, 2019·Zoological Science·Shiori MushaHideaki Tomura
Nov 12, 2016·Science China. Life Sciences·Xueping GongYuan Wang
Feb 2, 2019·The Journal of Clinical Investigation·Jane E Churpek, Emery H Bresnick

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Methods Mentioned

BETA
flow cytometry
fluorescence-activated cell sorting
immunoprecipitation
RNA-seq
FACS
ChIP
dissection
transfection

Software Mentioned

GraphPad
Excel

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