| First Author | Mehta C | Year | 2017 |
| Journal | Cell Rep | Volume | 20 |
| Issue | 12 | Pages | 2966-2979 |
| PubMed ID | 28930689 | Mgi Jnum | J:254246 |
| Mgi Id | MGI:6104187 | Doi | 10.1016/j.celrep.2017.08.090 |
| Citation | Mehta C, et al. (2017) Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program. Cell Rep 20(12):2966-2979 |
| abstractText | 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. |
