Position-specific binding of FUS to nascent RNA regulates mRNA length.
Position-specific binding of FUS to nascent RNA regulates mRNA length.
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DOI：
10.1101/gad.255737.114
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发表时间：
2015-05-15
影响因子：
10.5
通讯作者：
Ohno K
中科院分区：
文献类型：
--
作者：
Masuda A;Takeda J;Okuno T;Okamoto T;Ohkawara B;Ito M;Ishigaki S;Sobue G;Ohno K
超过一半的人类基因产生过早终止的多聚腺苷酸化短mRNA。增田等人表明，FUS经常聚集在新生RNA的另一个多聚腺苷酸化（阿帕）位点周围，使RNAP II停滞，并过早地终止神经元细胞中的转录。FUS对mRNA长度的位置特异性调节在神经元细胞中三分之二的转录物中是可操作的，其中富集了参与突触活动的基因。超过一半的人类基因产生过早终止的多聚腺苷酸化短mRNA。然而，基本的机制在很大程度上仍然难以捉摸。神经元细胞中FUS（融合在肉瘤中）的CLIP-seq（交联免疫沉淀[CLIP]结合深度测序）显示，FUS经常聚集在新生RNA的替代多聚腺苷酸化（阿帕）位点周围。RNA聚合酶II（RNAP II）的ChIP-seq（染色质免疫沉淀[ChIP]结合深度测序）表明，FUS使RNAP II停滞并过早终止转录。当阿帕位点位于FUS簇的上游时，FUS通过募集CPSF 160增强聚腺苷酸化并上调替代短转录物。相反，当阿帕位点位于FUS簇的下游时，聚腺苷酸化不被激活，并且FUS的RNAP II抑制作用导致替代短转录物的下调。CAGE-seq（与深度测序相结合的基因表达帽分析[CAGE]）和PolyA-seq（一种用于多聚腺苷酸化转录物3'端高通量测序的链特异性和定量方法）显示，FUS对mRNA长度的位置特异性调节在神经元细胞中三分之二的转录物中是可操作的，其中富集了参与突触活动的基因。
More than half of all human genes produce prematurely terminated polyadenylated short mRNAs. Masuda et al. show that FUS is frequently clustered around an alternative polyadenylation (APA) site of nascent RNA, stalls RNAP II, and prematurely terminates transcription in neuronal cells. Position-specific regulation of mRNA lengths by FUS is operational in two-thirds of transcripts in neuronal cells, with enrichment in genes involved in synaptic activities. More than half of all human genes produce prematurely terminated polyadenylated short mRNAs. However, the underlying mechanisms remain largely elusive. CLIP-seq (cross-linking immunoprecipitation [CLIP] combined with deep sequencing) of FUS (fused in sarcoma) in neuronal cells showed that FUS is frequently clustered around an alternative polyadenylation (APA) site of nascent RNA. ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing) of RNA polymerase II (RNAP II) demonstrated that FUS stalls RNAP II and prematurely terminates transcription. When an APA site is located upstream of an FUS cluster, FUS enhances polyadenylation by recruiting CPSF160 and up-regulates the alternative short transcript. In contrast, when an APA site is located downstream from an FUS cluster, polyadenylation is not activated, and the RNAP II-suppressing effect of FUS leads to down-regulation of the alternative short transcript. CAGE-seq (cap analysis of gene expression [CAGE] combined with deep sequencing) and PolyA-seq (a strand-specific and quantitative method for high-throughput sequencing of 3' ends of polyadenylated transcripts) revealed that position-specific regulation of mRNA lengths by FUS is operational in two-thirds of transcripts in neuronal cells, with enrichment in genes involved in synaptic activities.
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