UW-Madison Blood Research Program, Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI 53705, USA.
Cell Rep. 2017 Sep 19;20(12):2966-2979. doi: 10.1016/j.celrep.2017.08.090.
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.
造血发育需要转录因子 GATA-2，而 GATA-2 突变会导致多种病理，包括白血病。GATA-2 调节的增强子增加了造血干/祖细胞中的 Gata2 表达，并控制造血。+9.5kb 增强子在血管内皮细胞和造血干细胞（HSCs）中激活转录，其缺失会破坏 HSC 的生成。-77kb 增强子在髓系祖细胞中激活转录，其缺失会影响分化。由于+9.5 胚胎缺乏 HSC，因此不清楚+9.5 是否在祖细胞中起作用，或者祖细胞中 GATA-2 的表达是否仅需要-77。我们使用-77；+9.5 复合杂合（CH）小鼠进一步剖析了这些机制。胚胎致死性 CH 突变耗尽巨核细胞-红细胞祖细胞（MEPs）。虽然+9.5 足以生成 HSC，但-77 和+9.5 必须位于同一等位基因上才能诱导 MEPs。-77 通过诱导 GATA-1 和其他 GATA-2 靶基因产生成红细胞集落形成单位。增强子回路控制信号通路，协调 GATA 因子依赖的血液发育程序。
