Estrogen receptor beta impacts hormone-induced alternative mRNA splicing in breast cancer cells.
Estrogen receptor beta impacts hormone-induced alternative mRNA splicing in breast cancer cells.
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DOI：
10.1186/s12864-015-1541-1
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发表时间：
2015-05-09
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：
Dago DN;Scafoglio C;Rinaldi A;Memoli D;Giurato G;Nassa G;Ravo M;Rizzo F;Tarallo R;Weisz A
雌激素在乳腺癌（BC）的发生和发展中起着重要作用;当雌激素受体的两种亚型（ER α和ER β）共表达时，它们中的每一种都介导这些激素在BC细胞中的特异性作用。ER β被认为对ER α的致癌活性具有拮抗作用，因此被认为是一种抑癌基因。由于关于该受体亚型在乳腺癌应答性BC中的预后作用的临床证据仍然有限且相互矛盾，因此需要更多关于ER β在癌细胞中的生物学功能的知识。我们先前已经描述了来自BC细胞的ER β和ER α相互作用组，鉴定了两种受体的特异性和不同的蛋白质相互作用模式。特别是，我们确定了参与mRNA剪接和成熟的因子是ER α和ER β途径的重要组成部分。在这些发现的指导下，我们进行了RNA测序，以深入研究雌二醇在单独表达ER α或ER α和ER β的细胞中诱导的早期转录事件和RNA剪接模式的差异。外显子跳跃是雌二醇转录后调控中最丰富的剪接事件。我们鉴定了ER α单独和ER α + ER β诱导的几种剪接事件，首次证明ER β显著影响BC细胞中雌激素诱导的剪接，如ER β修饰ER α依赖性剪接的子集以及仅在ER β +细胞中存在剪接异构体所揭示的。特别地，我们观察到ER β + BC细胞系表现出比ER β-细胞多约2倍的剪接事件。有趣的是，我们通过将ER β和ER α结合位点的基因组位置与相应基因中雌二醇诱导的差异剪接相关联，确定了ER β介导的可变剪接的推定直接靶点。总而言之，这些结果表明ER β显着影响激素反应性BC细胞中雌激素诱导的早期转录和mRNA剪接，为ER β在这些肿瘤中的生物学作用提供了新的信息。本文的在线版本（doi：10.1186/s12864 - 015 - 1541 - 1）包含补充材料，可供授权用户使用。
Estrogens play an important role in breast cancer (BC) development and progression; when the two isoforms of the estrogen receptor (ERα and ERβ) are co-expressed each of them mediate specific effects of these hormones in BC cells. ERβ has been suggested to exert an antagonist role toward the oncogenic activities of ERα, and for this reason it is considered an oncosuppressor. As clinical evidence regarding a prognostic role for this receptor subtype in hormone-responsive BC is still limited and conflicting, more knowledge is required on the biological functions of ERβ in cancer cells. We have previously described the ERβ and ERα interactomes from BC cells, identifying specific and distinct patterns of protein interactions for the two receptors. In particular, we identified factors involved in mRNA splicing and maturation as important components of both ERα and ERβ pathways. Guided by these findings, here we performed RNA sequencing to investigate in depth the differences in the early transcriptional events and RNA splicing patterns induced by estradiol in cells expressing ERα alone or ERα and ERβ. Exon skipping was the most abundant splicing event in the post-transcriptional regulation by estradiol. We identified several splicing events induced by ERα alone and by ERα + ERβ, demonstrating for the first time that ERβ significantly affects estrogen-induced splicing in BC cells, as revealed by modification of a subset of ERα-dependent splicing by ERβ, as well as by the presence of splicing isoforms only in ERβ + cells. In particular, we observed that ERβ + BC cell lines exhibited around 2-fold more splicing events than the ERβ- cells. Interestingly, we identified putative direct targets of ERβ-mediated alternative splicing by correlating the genomic locations of ERβ and ERα binding sites with estradiol-induced differential splicing in the corresponding genes. Taken together, these results demonstrate that ERβ significantly affects estrogen-induced early transcription and mRNA splicing in hormone-responsive BC cells, providing novel information on the biological role of ERβ in these tumors. The online version of this article (doi:10.1186/s12864-015-1541-1) contains supplementary material, which is available to authorized users.
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影响因子：
56.9
作者：
Carninci, P;Kasukawa, T;Hayashizaki, Y
通讯作者：
Hayashizaki, Y
影响因子：
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Parker, MG
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4.8
作者：
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