Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation.
Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation.
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DOI：
10.1186/1471-2164-12-36
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发表时间：
2011-01-14
期刊：
影响因子：
4.4
通讯作者：
Weisz A
中科院分区：
文献类型：
--
作者：
Grober OM;Mutarelli M;Giurato G;Ravo M;Cicatiello L;De Filippo MR;Ferraro L;Nassa G;Papa MF;Paris O;Tarallo R;Luo S;Schroth GP;Benes V;Weisz A
雌激素受体α（ERα）和β（ERβ）是介导雌激素信号传导并定义乳腺癌（BC）的乳腺癌应答表型的转录因子（TF）。这两种受体可以被发现共表达，并发挥特定的，通常相反的作用，ERβ能够调节ERα对基因转录和细胞增殖的影响。ERβ在BC中经常丢失，其存在通常与疾病的更好预后相关。因此，在雌激素应答性BC细胞中识别ERβ的基因组靶标是阐明该受体在雌激素信号传导和肿瘤细胞生物学中的作用的关键步骤。在雌激素应答性、ERα阳性MCF-7细胞中表达全长ERβ可导致雌激素应答性细胞增殖显著降低，并对细胞转录组产生显著影响。通过ChIP-Seq，我们在雌激素刺激的细胞中鉴定了9702个ERβ和6024个ERα结合位点，包括ERβ、ERα或两种ER亚型占据的位点。对TF结合基质的搜索显示，鉴定的大多数结合位点包含一个或多个雌激素应答元件，其余的显示已知通过栓系介导ER与染色质相互作用的其他TF的结合基质，包括AP 2、E2 F和SP 1。在ERβ+和ERβ-细胞中，雌激素差异调节的921个基因中，有424个在10 kb内有一个或多个ERβ位点。这些推定的主要ERβ靶基因控制细胞增殖、死亡、分化、运动和粘附、信号转导和转录，这些关键细胞过程可能解释表达该ER亚型的肿瘤的生物学和临床表型。ERβ与几个miRNA基因和线粒体基因组紧密结合，表明该受体可能参与小的非编码RNA生物合成和线粒体基因组功能。结果表明，ERβ的绝大多数基因组靶点也可以结合ERα，这表明ERβ对乳腺癌应答性BC细胞基因组的总体作用主要取决于细胞中两种ER的相对浓度。
Estrogen receptors alpha (ERα) and beta (ERβ) are transcription factors (TFs) that mediate estrogen signaling and define the hormone-responsive phenotype of breast cancer (BC). The two receptors can be found co-expressed and play specific, often opposite, roles, with ERβ being able to modulate the effects of ERα on gene transcription and cell proliferation. ERβ is frequently lost in BC, where its presence generally correlates with a better prognosis of the disease. The identification of the genomic targets of ERβ in hormone-responsive BC cells is thus a critical step to elucidate the roles of this receptor in estrogen signaling and tumor cell biology. Expression of full-length ERβ in hormone-responsive, ERα-positive MCF-7 cells resulted in a marked reduction in cell proliferation in response to estrogen and marked effects on the cell transcriptome. By ChIP-Seq we identified 9702 ERβ and 6024 ERα binding sites in estrogen-stimulated cells, comprising sites occupied by either ERβ, ERα or both ER subtypes. A search for TF binding matrices revealed that the majority of the binding sites identified comprise one or more Estrogen Response Element and the remaining show binding matrixes for other TFs known to mediate ER interaction with chromatin by tethering, including AP2, E2F and SP1. Of 921 genes differentially regulated by estrogen in ERβ+ vs ERβ- cells, 424 showed one or more ERβ site within 10 kb. These putative primary ERβ target genes control cell proliferation, death, differentiation, motility and adhesion, signal transduction and transcription, key cellular processes that might explain the biological and clinical phenotype of tumors expressing this ER subtype. ERβ binding in close proximity of several miRNA genes and in the mitochondrial genome, suggests the possible involvement of this receptor in small non-coding RNA biogenesis and mitochondrial genome functions. Results indicate that the vast majority of the genomic targets of ERβ can bind also ERα, suggesting that the overall action of ERβ on the genome of hormone-responsive BC cells depends mainly on the relative concentration of both ERs in the cell.
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影响因子：
14.9
作者：
Bhat-Nakshatri P;Wang G;Collins NR;Thomson MJ;Geistlinger TR;Carroll JS;Brown M;Hammond S;Srour EF;Liu Y;Nakshatri H
通讯作者：
Nakshatri H
影响因子：
4.7
作者：
Buterin, Tonko;Koch, Caroline;Naegeli, Hanspeter
通讯作者：
Naegeli, Hanspeter
DOI：
10.1073/pnas.0906947106
发表时间：
2009-09-15
影响因子：
11.1
作者：
Castellano, Leandro;Giamas, Georgios;Stebbing, Justin
通讯作者：
Stebbing, Justin
影响因子：
3.3
作者：
Caporali, S;Imai, M;Weisz, A
通讯作者：
Weisz, A
影响因子：
4.8
作者：
Cowley, SM;Hoare, S;Parker, MG
通讯作者：
Parker, MG