Progenitor Stage-Specific Activity of a cis-Acting Double GATA Motif for Gata1 Gene Expression
Progenitor Stage-Specific Activity of a cis-Acting Double GATA Motif for Gata1 Gene Expression
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DOI：
10.1128/mcb.01011-14
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发表时间：
2015-03-01
影响因子：
5.3
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
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作者：
Moriguchi, Takashi;Suzuki, Mikiko;Yamamoto, Masayuki
GATA1 是红细胞生成的主要调节因子，其表达受到多个离散顺式作用元件的调节。在本研究中，我们使用 Gata1 细菌人工染色体 (BAC)-转基因绿色荧光蛋白 (GFP) 报告基因 (G1BAC-GFP) 小鼠系统检查启动子近端双 GATA (dbGATA) 基序的活性。 dbGATA 基序的删除导致造血祖细胞中 GFP 表达显着减少，而红细胞中 GFP 表达得以维持。一致地，在 dbGATA 基序的种系缺失的小鼠（Gata1（Delta dbGATA）小鼠）中，祖细胞中的 GATA1 表达显着降低。 GATA1 表达的抑制与祖细胞中 GATA2 水平的代偿性增加有关。当我们将Gata1(Delta dbGATA)小鼠与Gata2亚等位突变小鼠(Gata2(fGN/fGN)小鼠)杂交时，Gata1(Delta dbGATA)::Gata(2fGN/fGN)复合突变小鼠的祖细胞数量显着减少，而两组单突变小鼠均保留祖细胞并存活至成年，这表明GATA1和GATA2之间的功能冗余祖先。同时，在成红细胞中，dbGATA 位点缺失对 Gata1 表达的影响很微妙，这表明 GATA1 结合增加，并且 Delta dbGATA 基因座的第一个内含子 GATA 基序周围活性组蛋白标记的积累增加。因此，这些结果揭示了 dbGATA 基序在维持造血祖细胞中 Gata1 表达中的新作用，以及 dbGATA 位点和成红细胞中第一个内含子 GATA 基序之间的功能补偿。
GATA1 is a master regulator of erythropoiesis, expression of which is regulated by multiple discrete cis-acting elements. In this study, we examine the activity of a promoter-proximal double GATA (dbGATA) motif, using a Gata1 bacterial artificial chromosome (BAC)-transgenic green fluorescent protein (GFP) reporter (G1BAC-GFP) mouse system. Deletion of the dbGATA motif led to significant reductions in GFP expression in hematopoietic progenitors, while GFP expression was maintained in erythro-blasts. Consistently, in mice with a germ line deletion of the dbGATA motif (Gata1(Delta dbGATA) mice), GATA1 expression in progenitors was significantly decreased. The suppressed GATA1 expression was associated with a compensatory increase in GATA2 levels in progenitors. When we crossed Gata1(Delta dbGATA) mice with Gata2 hypomorphic mutant mice (Gata2(fGN/fGN) mice), the Gata1(Delta dbGATA):: Gata(2fGN/fGN) compound mutant mice succumbed to a significant decrease in the progenitor population, whereas both groups of single mutant mice maintained progenitors and survived to adulthood, indicating the functional redundancy between GATA1 and GATA2 in progenitors. Meanwhile, the effects of the dbGATA site deletion on Gata1 expression were subtle in erythroblasts, which showed increased GATA1 binding and enhanced accumulation of active histone marks around the 1st-intron GATA motif of the Delta dbGATA locus. These results thus reveal a novel role of the dbGATA motif in the maintenance of Gata1 expression in hematopoietic progenitors and a functional compensation between the dbGATA site and the 1st-intron GATA motif in erythroblasts.