The binding of the ubiquitous transcription factor Sp1 at the locus control region represses the expression of β-like globin genes
The binding of the ubiquitous transcription factor Sp1 at the locus control region represses the expression of β-like globin genes
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DOI：
10.1073/pnas.0502041102
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发表时间：
2005-07-12
影响因子：
11.1
通讯作者：
Kan, YW
中科院分区：
文献类型：
--
作者：
Feng, DX;Kan, YW
为了研究转录因子Sp1在β-珠蛋白样基因激活中的功能，我们分析了Sp1、胎儿Kruppel样因子2（FKLF 2）和相关因子在人胎肝和小鼠红白血病杂交细胞（A181 γ细胞）中的人β-珠蛋白基因座的募集，该细胞包含一个人类11号染色体的单拷贝。Sp1结合在整个β基因座的顺式元件的GT盒上，但在A181 γ细胞分化后，它被磷酸化并在DNA酶I超敏位点（HS）2、HS 3、HS 4和人β-珠蛋白基因启动子上丢失。FKLF 2与HS 2和HS 3的结合未发生变化。组蛋白去乙酰化酶1，其可以被Spl募集，在分化后也在HS 2和HS 3上丢失，导致组蛋白3和4在人β-珠蛋白基因座上的乙酰化。我们先前检测到在A181 γ分化后在β-珠蛋白基因座上的体内GT足迹。在这里，我们报告，分化后，p300/CREB结合蛋白相关因子被FKLF 2募集到基因座控制区，使人β-珠蛋白基因座的组蛋白3和4乙酰化。我们的结果表明Spl是红细胞终末分化期间β样球蛋白基因转录的抑制剂。其磷酸化和释放允许红系特异性FKLF 2或红系Kruppel样因子与其他红系特异性转录因子相互作用以启动β样珠蛋白基因的转录。
To investigate the function of transcription factor Sp1 in beta-like globin gene activation, we analyzed the recruitment of Sp1, fetal Kruppel-like factor 2 (FKLF2), and related factors at the human beta-globin locus in a human fetal liver and mouse erythroleukemia hybrid cell (A181 gamma cell) that contains a single copy of human chromosome 11. Sp1 binds at the GT boxes of the cis-elements throughout the beta-locus, but it is phosphorylated and lost over DNase I hypersensitive site (HS)2, HS3, HS4, and the human beta-globin gene promoter after A181 gamma cell differentiation. The binding of FKLF2 at HS2 and HS3 was unchanged. Histone deacetylase 1, which could be recruited by Spl, is also lost over HS2 and HS3 after differentiation, resulting in the acetylation of histones 3 and 4 across the human beta-globin locus. We previously detected in vivo GT footprints over the beta-globin locus after A181 gamma differentiation. Here, we report that after differentiation, the p300/CREB-binding protein-associated factor is recruited by FKLF2 to the locus control region to acetylate histones 3 and 4 at the human beta-globin gene locus. Our results suggest that Spl is an inhibitor of beta-like globin gene transcription during erythroid terminal differentiation. Its phosphorylation and release allow the erythroid-specific FKLF2 or erythroid Kruppel-like factor to interact with other erythroid-specific transcription factors to initiate the transcription of beta-like globin genes.