[PDF][PDF] Integrating enhancer mechanisms to establish a hierarchical blood development program
Cell reports, 2017•cell.com
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 …
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 …
Summary
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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