Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program

Publication date: 19 September 2017 Source:Cell Reports, Volume 20, Issue 12 Author(s): Charu Mehta, Kirby D. Johnson, Xin Gao, Irene M. Ong, Koichi R. Katsumura, Skye C. McIver, Erik A. Ranheim, Emery H. Bresnick 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. Graphical abstract Teaser Mutations of GATA2 and its enhancers cause immunodeficiency, myelody...
Source: Cell Reports - Category: Cytology Source Type: research