Mapping ERβ genomic binding sites reveals unique genomic features and identifies EBF1 as an ERβ interactor.
Mapping ERβ genomic binding sites reveals unique genomic features and identifies EBF1 as an ERβ interactor.
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DOI：
10.1371/journal.pone.0071355
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Greene GL
中科院分区：
文献类型：
--
作者：
Le TP;Sun M;Luo X;Kraus WL;Greene GL
经过众多实验室的努力，人们对雌激素及其受体ER-α和ER-β的作用有了更深入的了解。然而，ERβ在细胞生理学中的许多靶点仍然难以捉摸。本研究以稳定表达Flag.ERβ的C4-12/Flag.ERβ细胞株为研究对象，在没有ERβ干扰的情况下，对ERα的基因组功能进行了研究。在这些细胞中绘制ERβ结合位点的图显示了ERβ独特的分布和基序浓缩模式。伴随着我们的作图结果，在相同的处理时间对细胞进行新生RNA图谱分析。结合结果可以识别ERβ的靶基因。基因本体论分析表明，ERβ靶点在分化、发育和凋亡过程中具有丰富的功能。同时，E2处理抑制了这些细胞的增殖。在ERβ结合位点中，虽然最普遍的结合基序是规范的ERE，但已知的ER相互作用基序也富含在ERβ结合位点中。此外，在丰富的结合基序中有GFI、REST和EBF1，它们是这些细胞中ERβ结合位点所独有的。进一步的研究证实了EBF1与雌激素受体之间的联系，雌激素受体有利于受体的N-末端区域。此外，EBF1在蛋白水平上负向调节ERs。综上所述，通过在我们的细胞模型中研究ERβ的基因组功能，我们证实了ERβ的抗增殖作用，并发现了ERβ与EBF1的新的相互作用，这在正常生理中具有多种意义。
Considerable effort by numerous laboratories has resulted in an improved understanding of estrogen and SERM action mediated by the two estrogen receptors, ERα and ERβ. However, many of the targets for ERβ in cell physiology remain elusive. Here, the C4-12/Flag.ERβ cell line which stably expressed Flag.ERβ is used to study ERβ genomic functions without ERα interference. Mapping ERβ binding sites in these cells reveals ERβ unique distribution and motif enrichment patterns. Accompanying our mapping results, nascent RNA profiling is performed on cells at the same treatment time. The combined results allow the identification of ERβ target genes. Gene ontology analysis reveals that ERβ targets are enriched in differentiation, development and apoptosis. Concurrently, E2 treatment suppresses proliferation in these cells. Within ERβ binding sites, while the most prevalent binding motif is the canonical ERE, motifs of known ER interactors are also enriched in ERβ binding sites. Moreover, among enriched binding motifs are those of GFI, REST and EBF1, which are unique to ERβ binding sites in these cells. Further characterization confirms the association between EBF1 and the estrogen receptors, which favors the N-terminal region of the receptor. Furthermore, EBF1 negatively regulates ERs at the protein level. In summary, by studying ERβ genomic functions in our cell model, we confirm the anti-proliferative role of ERβ and discover the novel cross talk of ERβ with EBF1 which has various implications in normal physiology.
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