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Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program.

ABSTRACT: Hematopoietic development requires the transcription factor GATA-2, and GATA-2 mutations cause diverse pathologies, including leukemia. GATA-2-regulated enhancers increase Gata2 expression in hematopoietic stem/progenitor cells and control hematopoiesis. The +9.5-kb enhancer activates transcription in endothelium and hematopoietic stem cells (HSCs), and its deletion abrogates HSC generation. The -77-kb enhancer activates transcription in myeloid progenitors, and its deletion impairs differentiation. Since +9.5-/- embryos are HSC deficient, it was unclear whether the +9.5 functions in progenitors or if GATA-2 expression in progenitors solely requires -77. We further dissected the mechanisms using -77;+9.5 compound heterozygous (CH) mice. The embryonic lethal CH mutation depleted megakaryocyte-erythrocyte progenitors (MEPs). While the +9.5 suffices for HSC generation, the -77 and +9.5 must reside on one allele to induce MEPs. The -77 generated burst-forming unit-erythroid through the induction of GATA-1 and other GATA-2 targets. The enhancer circuits controlled signaling pathways that orchestrate a GATA factor-dependent blood development program.

SUBMITTER: Mehta C

PROVIDER: S-EPMC5618720 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program.

Mehta Charu C Johnson Kirby D KD Gao Xin X Ong Irene M IM Katsumura Koichi R KR McIver Skye C SC Ranheim Erik A EA Bresnick Emery H EH

Cell reports 20170901 12

Hematopoietic development requires the transcription factor GATA-2, and GATA-2 mutations cause diverse pathologies, including leukemia. GATA-2-regulated enhancers increase Gata2 expression in hematopoietic stem/progenitor cells and control hematopoiesis. The +9.5-kb enhancer activates transcription in endothelium and hematopoietic stem cells (HSCs), and its deletion abrogates HSC generation. The -77-kb enhancer activates transcription in myeloid progenitors, and its deletion impairs differentiat ...[more]

PMID: 28930689

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Dataset Information

Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program.

Publications

Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program.

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