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首页 » 中国科学院 » Nucl Acids Res:冯英等揭示SRSF10调控mRNA选择性剪接的新机制

Nucl Acids Res:冯英等揭示SRSF10调控mRNA选择性剪接的新机制

来源:上海生命科学研究院 2014-01-22 21:51

1月18日,Nucleic Acids Research在线发表了中科院上海生命科学研究院营养科学研究所研究员冯英组的最新研究进展:Transcriptome analysis of alternative splicing events regulated by SRSF10 reveals position-dependent splicing modulation,该研究基于高通量转录组测序(RNA-seq)技术结合生物信息分析,首次揭示了选择性剪接蛋白SRSF10在细胞内调节的靶底物以及其调控mRNA选择性剪接的机制。

近年来,随着二代测序技术的飞速发展,测序已成为研究基因组和转录组的重要手段之一。高通量转录组测序技术(RNA-seq)可用于检测基因表达差异、融合基因、未知或稀有转录本、以及mRNA选择性剪接等研究领域。

SRSF10是经典的SR蛋白家族成员之一,已有研究表明,SRSF10在体外是一个序列特异性的剪接激活蛋白,但是其在体内的剪接调控靶点及作用机制,目前仍然不清楚。

在冯英指导下,博士生周雪霞和博士后吴文武等利用RNA-seq技术,并结合自主研发的选择性剪接java软件(软件名称:Alternative Splicing Detector:ASD, 网址:http://www.novelbio.com/asd/ASD.html),在鸡细胞系DT40中,寻找受SRSF10调节的体内剪接底物。研究发现, SRSF10同时具有增强外显子接入和抑制外显子接入的双重功能;Motif分析发现,外显子的接入与否与SRSF10的结合位点在调控外显子上的分布有关。进一步研究表明:SRSF10所调控的剪接事件多为应激或凋亡相关的基因。SRSF10敲除的DT40细胞对内质网应激诱导的凋亡更为敏感,提示其可能通过调节应激相关基因的选择性剪接,控制着内质网应激下的细胞存活能力。

该研究加深了人们对于SRSF10在体内调节的剪接网络和机制的理解,为深入研究SRSF10在细胞存活能力中的作用和机制提供了新线索。

该研究获得了国家科技部、基金委、中科院百人计划和中国博士后基金等项目的资助。 (生物谷Bioon.com)

生物谷推荐的英文摘要:

Nucleic Acids Research          doi: 10.1093/nar/gkt1387

Transcriptome analysis of alternative splicing events regulated by SRSF10 reveals position-dependent splicing modulation.

Zhou X, Wu W, Li H, Cheng Y, Wei N, Zong J, Feng X, Xie Z, Chen D, Manley JL, Wang H, Feng Y.

Splicing factor SRSF10 is known to function as a sequence-specific splicing activator. Here, we used RNA-seq coupled with bioinformatics analysis to identify the extensive splicing network regulated by SRSF10 in chicken cells. We found that SRSF10 promoted both exon inclusion and exclusion. Motif analysis revealed that SRSF10 binding to cassette exons was associated with exon inclusion, whereas the binding of SRSF10 within downstream constitutive exons was associated with exon exclusion. This positional effect was further demonstrated by the mutagenesis of potential SRSF10 binding motifs in two minigene constructs. Functionally, many of SRSF10-verified alternative exons are linked to pathways of stress and apoptosis. Consistent with this observation, cells depleted of SRSF10 expression were far more susceptible to endoplasmic reticulum stress-induced apoptosis than control cells. Importantly, reconstituted SRSF10 in knockout cells recovered wild-type splicing patterns and considerably rescued the stress-related defects. Together, our results provide mechanistic insight into SRSF10-regulated alternative splicing events in vivo and demonstrate that SRSF10 plays a crucial role in cell survival under stress conditions.

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