非常有意思的是，在高级灵长类和人类当中，5S-OT RNA获取了调控多个基因可变剪切的新功能。在高级灵长类和人类中，5S-OT中插入了一个反义Alu序列，并因此同时产生了一个多嘧啶（polypyrimidine-tract， Py）位点。Alu是一种灵长类特异的基因组短重复序列，而人类基因组DNA中约10%的序列为Alu的正向或反向序列。随后在人细胞中的研究发现，人类5S-OT RNA可以通过其Py位点招募参与pre-mRNA剪切的蛋白质U2AF65，进而通过5S-OT RNA中的反向Alu序列与靶标pre-mRNA当中的正向Alu序列的互补配对、将U2AF65蛋白带到受其调控的pre-mRNA上。非灵长类动物的5S-OT RNA不具有Py位点、不与U2AF65蛋白有相互作用、因而不能调控相应物种中的mRNA可变剪切。
该发现一个直接的应用是可以利用人类5S-OT RNA的这一调控机理、通过人工设计的、针对特定基因序列的“改装版”5S-OT来调控特定基因的剪切。在文章中、把人5S-OT RNA中的反义Alu序列换为与特定基因pre-mRNA互补的序列、即可调控该基因的可变剪切。很多人类疾病与基因剪切异常相关、未来有可能以这一发现为基础发展出生物技术来“纠正”基因的可变剪切。
文章的共同第一作者为博士生胡珊珊和硕士王小林。研究得到了科技部、中科院、国家基金委、以及中科大非编码RNA功能及功能机理创新团队的经费支持。
Shanshan Hu*, Xiaolin Wang*, Ge Shan. Insertion of an Alu element in an lncRNA leads to primate specific modulation of alternative splicing. Nat. Struct. Mol. Bio. 2016, Online (doi:10.1038/nsmb.3302).
论文链接：http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.3302.html
ABSTRACT
Noncoding RNAs, mobile elements, and alternative splicing are all critical for the regulation of gene expression. Here we show that a conserved noncoding RNA acquires a new function due to the insertion of a mobile element. We identified a noncoding RNA, termed 5S-OT, which is transcribed from 5S rDNA loci in eukaryotes including fission yeast and mammals. 5S-OT plays a cis role in regulating the transcription of 5S rRNA in mice and humans. In the anthropoidea suborder of primates, an antisense Alu element has been inserted at the 5S-OT locus. We found that in human cells, 5S-OT regulates alternative splicing of multiple genes in trans via Alu/anti-Alu pairing with target genes and by interacting with the splicing factor U2AF65. This trans effect of 5S-OT in splicing might be exploited in biotechnological applications.