E2F mediates enhanced alternative polyadenylation in proliferation.
E2F mediates enhanced alternative polyadenylation in proliferation.
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DOI：
10.1186/gb-2012-13-7-r59
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发表时间：
2012-07-02
期刊：
影响因子：
12.3
通讯作者：
Agami R
中科院分区：
文献类型：
--
作者：
Elkon R;Drost J;van Haaften G;Jenal M;Schrier M;Oude Vrielink JA;Agami R
大多数哺乳动物基因的 3' UTR 中含有多个 Poly(A) 位点。选择性切割和聚腺苷酸化正在成为基因调控的重要层，因为它们产生 3' UTR 不同的转录亚型，从而调节基因对 3' UTR 介导的调控的反应。最近发现，3' UTR 近端 Poly(A) 位点的增强裂解导致整体 3' UTR 缩短，与增殖和癌症有关。然而，调节这种增强的替代多聚腺苷酸化的机制尚不清楚。在这里，我们在转录组范围内探索了与细胞增殖和肿瘤转化相关的替代多腺苷酸化事件。我们将深度测序技术应用于两个人类细胞模型中的聚腺苷酸位点的识别和定量，每个模型都在增殖、停滞和转化状态下进行检查。在这两个细胞系统中，我们观察到与增殖相关的整体 3' UTR 缩短，这种联系明显强于与转化的联系。此外，我们发现增殖还与内含子 Poly(A) 位点的增强裂解有关。最后，我们发现编码 3' 端加工蛋白的一组基因的表达水平在增殖过程中整体升高，并且 E2F 转录因子有助于这种调节。我们的结果全面鉴定了与细胞增殖和转化相关的替代多腺苷酸化事件，并证明增殖条件下增强的替代多腺苷酸化不仅导致整体3'UTR缩短，而且还导致内含子的过早裂解增强。我们的结果还表明，E2F 介导的 3' 末端加工基因的共转录调控是将增强的选择性多聚腺苷酸化与增殖联系起来的机制之一。
The majority of mammalian genes contain multiple poly(A) sites in their 3' UTRs. Alternative cleavage and polyadenylation are emerging as an important layer of gene regulation as they generate transcript isoforms that differ in their 3' UTRs, thereby modulating genes' response to 3' UTR-mediated regulation. Enhanced cleavage at 3' UTR proximal poly(A) sites resulting in global 3' UTR shortening was recently linked to proliferation and cancer. However, mechanisms that regulate this enhanced alternative polyadenylation are unknown. Here, we explored, on a transcriptome-wide scale, alternative polyadenylation events associated with cellular proliferation and neoplastic transformation. We applied a deep-sequencing technique for identification and quantification of poly(A) sites to two human cellular models, each examined under proliferative, arrested and transformed states. In both cell systems we observed global 3' UTR shortening associated with proliferation, a link that was markedly stronger than the association with transformation. Furthermore, we found that proliferation is also associated with enhanced cleavage at intronic poly(A) sites. Last, we found that the expression level of the set of genes that encode for 3'-end processing proteins is globally elevated in proliferation, and that E2F transcription factors contribute to this regulation. Our results comprehensively identify alternative polyadenylation events associated with cellular proliferation and transformation, and demonstrate that the enhanced alternative polyadenylation in proliferative conditions results not only in global 3' UTR shortening but also in enhanced premature cleavage in introns. Our results also indicate that E2F-mediated co-transcriptional regulation of 3'-end processing genes is one of the mechanisms that links enhanced alternative polyadenylation to proliferation.
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