Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan; Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan; Department of Molecular Hematology, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
Genes Cells. 2013 Nov;18(11):921-33. doi: 10.1111/gtc.12086. Epub 2013 Aug 1.
Transcription factor GATA2 is highly expressed in hematopoietic stem cells and progenitors, whereas its expression declines after erythroid commitment of progenitors. In contrast, the start of GATA1 expression coincides with the erythroid commitment and increases along with the erythroid differentiation. We refer this dynamic transition of GATA factor expression to as the 'GATA factor switching'. Here, we examined contribution of the GATA factor switching to the erythroid differentiation. In Gata1-knockdown embryos that concomitantly express Gata2-GFP reporter, high-level expression of GFP reporter was detected in accumulated immature hematopoietic cells with impaired differentiation, demonstrating that GATA1 represses Gata2 gene expression in hematopoietic progenitors in vivo. We have conducted chromatin immunoprecipitation (ChIP) on microarray analyses of GATA2 and GATA1, and results indicate that the GATA1-binding sites widely overlap with the sites pre-occupied by GATA2 before the GATA1 expression. Importantly, erythroid genes harboring GATA boxes bound by both GATA1 and GATA2 tend to be expressed in immature erythroid cells, whereas those harboring GATA boxes to which GATA1 binds highly but GATA2 binds only weakly are important for the mature erythroid cell function. Our results thus support the contention that preceding binding of GATA2 helps the following binding of GATA1 and thereby secures smooth expression of the transient-phase genes.
转录因子 GATA2 在造血干细胞和祖细胞中高度表达，而其表达在祖细胞向红系分化后下降。相比之下，GATA1 的表达始于红系分化，并随着红系分化而增加。我们将 GATA 因子表达的这种动态转变称为“GATA 因子转换”。在这里，我们研究了 GATA 因子转换对红细胞分化的贡献。在同时表达 Gata2-GFP 报告基因的 Gata1 敲低胚胎中，在积累的未成熟造血细胞中检测到 GFP 报告基因的高表达，这些细胞分化受损，表明 GATA1 在体内抑制造血祖细胞中 Gata2 基因的表达。我们对 GATA2 和 GATA1 进行了染色质免疫沉淀（ChIP）分析，结果表明，在 GATA1 表达之前，GATA1 结合位点广泛与 GATA2 预先占据的位点重叠。重要的是，含有 GATA 盒的红细胞基因，这些 GATA 盒被 GATA1 和 GATA2 共同结合，往往在未成熟的红细胞中表达，而那些含有 GATA 盒的基因，GATA1 高度结合但 GATA2 结合较弱，对于成熟红细胞的功能很重要。因此，我们的研究结果支持这样一种观点，即 GATA2 的先结合有助于 GATA1 的后续结合，从而确保了瞬态基因的顺利表达。
