Cell Reports (Sep 2017)

Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program

  • Charu Mehta,
  • Kirby D. Johnson,
  • Xin Gao,
  • Irene M. Ong,
  • Koichi R. Katsumura,
  • Skye C. McIver,
  • Erik A. Ranheim,
  • Emery H. Bresnick

DOI
https://doi.org/10.1016/j.celrep.2017.08.090
Journal volume & issue
Vol. 20, no. 12
pp. 2966 – 2979

Abstract

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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.

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