β-globin active chromatin hub formation in differentiating erythroid cells and in p45 NF-E2 knock-out mice
β-globin active chromatin hub formation in differentiating erythroid cells and in p45 NF-E2 knock-out mice
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DOI：
10.1074/jbc.m701159200
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发表时间：
2007-06-01
影响因子：
4.8
通讯作者：
de Laat, Wouter
中科院分区：
文献类型：
--
作者：
Kooren, Jurgen;Palstra, Robert-Jan;de Laat, Wouter
在体内红系分化期间，β-珠蛋白基因的表达从基础水平进展到异常高的水平。高表达依赖于基因座控制区（LCR），并与更频繁的LCR基因接触相一致。这些接触是在活性染色质枢纽（ACH）的背景下建立的，ACH是一种空间染色质构型，其中LCR与其他调控序列一起朝向活性β-珠蛋白样基因形成环。在这里，我们使用最近建立的I/11细胞作为模型系统，忠实地再现了体内红系分化程序，以研究伴随ACH形成的分子事件。在I/11细胞诱导后，组蛋白修饰发生变化，ACH形成，β-珠蛋白样基因以与体内观察到的相似的速率转录。频繁的LCR基因接触的建立与聚合酶更有效地加载到β-珠蛋白启动子上相一致。转录因子加塔-1和EKLF与基因座的结合，尽管先前显示是必需的，但不足以形成ACH。此外，我们使用基因敲除小鼠表明，红系转录因子p45 NF-E2，这已经牵连在β-珠蛋白基因调控，是β-珠蛋白ACH形成的抑制剂。
Expression of the beta-globin genes proceeds from basal to exceptionally high levels during erythroid differentiation in vivo. High expression is dependent on the locus control region (LCR) and coincides with more frequent LCR-gene contacts. These contacts are established in the context of an active chromatin hub (ACH), a spatial chromatin configuration in which the LCR, together with other regulatory sequences, loops toward the active beta-globin-like genes. Here, we used recently established I/11 cells as a model system that faithfully recapitulates the in vivo erythroid differentiation program to study the molecular events that accompany and underlie ACH formation. Upon I/11 cell induction, histone modifications changed, the ACH was formed, and the beta-globin-like genes were transcribed at rates similar to those observed in vivo. The establishment of frequent LCR-gene contacts coincided with a more efficient loading of polymerase onto the beta-globin promoter. Binding of the transcription factors GATA-1 and EKLF to the locus, although previously shown to be required, was not sufficient for ACH formation. Moreover, we used knock-out mice to show that the erythroid transcription factor p45 NF-E2, which has been implicated in beta-globin gene regulation, is dispensable for beta-globin ACH formation.