Human TREX component Thoc5 affects alternative polyadenylation site choice by recruiting mammalian cleavage factor I.
Human TREX component Thoc5 affects alternative polyadenylation site choice by recruiting mammalian cleavage factor I.
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DOI：
10.1093/nar/gkt414
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发表时间：
2013-08
影响因子：
14.9
通讯作者：
Ohkawa Y
中科院分区：
文献类型：
--
作者：
Katahira J;Okuzaki D;Inoue H;Yoneda Y;Maehara K;Ohkawa Y
转录输出复合体（TREX）将mRNA转录、加工和核输出结合在一起。研究人员发现，CFIm是一种异四聚体蛋白复合物哺乳动物切割因子I （CFIm）的一个大亚基，与人类TREX的一种成分Thoc5共纯化，CFIm参与了多聚腺苷化位点的选择。使用针对TREX不同组分的抗体进行免疫沉淀表明，这两种复合物很可能通过Thoc5和CFIm68之间的相互作用相互作用。利用人HeLa细胞进行的微阵列分析显示，Thoc5敲低时，一组基因的表达存在差异。值得注意的是，Thoc5的缺失选择性地减弱了远端而非近端聚腺苷化位点的mrna表达，这反映了cim68的缺失。染色质免疫沉淀结合高通量测序（ChIP-Seq）显示，CFIm68优先与基因的5′区相关；引人注目的是，Thoc5敲除后，CFIm68的5′峰在全球范围内显著降低。我们提出了一个模型，在这个模型中，人类Thoc5通过将CFIm68共转录负载到靶基因上来控制聚腺苷化位点的选择。
The transcription-export complex (TREX) couples mRNA transcription, processing and nuclear export. We found that CFIm68, a large subunit of a heterotetrameric protein complex mammalian cleavage factor I (CFIm), which is implicated in alternative polyadenylation site choice, co-purified with Thoc5, a component of human TREX. Immunoprecipitation using antibodies against different components of TREX indicated that most likely both complexes interact via an interaction between Thoc5 and CFIm68. Microarray analysis using human HeLa cells revealed that a subset of genes was differentially expressed on Thoc5 knockdown. Notably, the depletion of Thoc5 selectively attenuated the expression of mRNAs polyadenylated at distal, but not proximal, polyadenylation sites, which phenocopied the depletion of CFIm68. Chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq) indicated that CFIm68 preferentially associated with the 5′ regions of genes; strikingly, the 5′ peak of CFIm68 was significantly and globally reduced on Thoc5 knockdown. We suggest a model in which human Thoc5 controls polyadenylation site choice through the co-transcriptional loading of CFIm68 onto target genes.
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