Gao X, Wu T, Johnson KD, Lahvic JL, Ranheim EA, Zon LI, Bresnick EH. GATA Factor-G-Protein-Coupled Receptor Circuit Suppresses Hematopoiesis. Stem Cell Reports. 2016 Mar 08; 6(3):368-82.

Citation

Gao X, Wu T, Johnson KD, Lahvic JL, Ranheim EA, Zon LI, Bresnick EH. 2016. GATA Factor-G-Protein-Coupled Receptor Circuit Suppresses Hematopoiesis. Stem cell reports. 6(3):368-82. Pubmed: 26905203 DOI:S2213-6711(16)00025-4

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.

Related Faculty

Leonard Zon, M.D.

Zon Lab

The Zon laboratory aims to dissect how assaults to the hematopoietic system cause severe diseases such as leukemias, lymphomas, and anemias. They investigate hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish.