Lineage-specific combinatorial action of enhancers regulates mouse erythroid Gata1 expression
Lineage-specific combinatorial action of enhancers regulates mouse erythroid Gata1 expression
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DOI：
10.1182/blood-2009-07-232876
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发表时间：
2010-04-29
期刊：
影响因子：
20.3
通讯作者：
Vyas, Paresh
中科院分区：
文献类型：
--
作者：
Drissen, Roy;Guyot, Boris;Vyas, Paresh
Gata 1表达的精确时空控制在早期造血祖细胞中是必需的，以确定红细胞/巨核细胞与粒细胞/单核细胞谱系输出，以及在红细胞和巨核细胞的后续分化中。小鼠Gata 1 IE（第一外显子红细胞）启动子mHS-3.5上游的增强子元件可指导红细胞和巨核细胞表达。然而，这种元素的缺失只消融巨核细胞，这意味着额外的元素具有红细胞特异性。在这里，我们确定了一个双DNaseI超敏位点，mHS-25/6，在原代细胞中具有红细胞活性，但不具有巨核细胞活性。它结合红系细胞中的激活转录因子复合物，在那里它也与Gata 1启动子物理接触。胚胎干细胞中mHS-25/6或mHS-3.5的缺失对体外红细胞分化只有适度的影响，而这两种元素的缺失会消除原始和定型红细胞生成，几乎完全丧失Gata 1表达。令人惊讶的是，Gata 2表达也伴随着低，表明这两个因素之间的相互作用比目前设想的更复杂。因此，尽管mHS-3.5单独足以用于巨核细胞发育，但mHS-3.5和mHS-25/6共同调节红系Gata 1表达，表明Gata 1顺式元件使用的谱系特异性差异对这2种细胞类型的发育很重要。（血。2010; 115（17）：3463-3471）
Precise spatiotemporal control of Gata1 expression is required in both early hematopoietic progenitors to determine erythroid/megakaryocyte versus granulocyte/monocyte lineage output and in the subsequent differentiation of erythroid cells and megakaryocytes. An enhancer element upstream of the mouse Gata1 IE (1st exon erythroid) promoter, mHS-3.5, can direct both erythroid and megakaryocytic expression. However, loss of this element ablates only megakaryocytes, implying that an additional element has erythroid specificity. Here, we identify a double DNaseI hypersensitive site, mHS-25/6, as having erythroid but not megakaryocytic activity in primary cells. It binds an activating transcription factor complex in erythroid cells where it also makes physical contact with the Gata1 promoter. Deletion of mHS-25/6 or mHS-3.5 in embryonic stem cells has only a modest effect on in vitro erythroid differentiation, whereas loss of both elements ablates both primitive and definitive erythropoiesis with an almost complete loss of Gata1 expression. Surprisingly, Gata2 expression was also concomitantly low, suggesting a more complex interaction between these 2 factors than currently envisaged. Thus, whereas mHS-3.5 alone is sufficient for megakaryocytic development, mHS-3.5 and mHS-25/6 collectively regulate erythroid Gata1 expression, demonstrating lineage-specific differences in Gata1 cis-element use important for development of these 2 cell types. (Blood. 2010; 115(17): 3463-3471)