Nature：基因表达调控机制新发现

　　

生物通报道，麻省理工生物学系，哈佛-麻省理工联合卫生科学与技术实验室，瑞典卡罗琳斯卡医学院细胞和分子生物学系，Illumina公司，白头生物医学研究所，国立基因组研究中心的科学家近期解开了mRNA在不同组织中的选择性剪接差异之谜，相关的文章发表在11月2日Nature online版上。

 

生物学家发现，几乎所有的基因都不止表达一种mRNA，结果表达不同的蛋白。而完成这一过程的是生物体内的选择性剪接机制。因此，同一个基因可产生不同的mRNA，不同的蛋白亚型，这些蛋白可能功能相似也可能功能相左。

 

研究者对15种不同的组织和细胞系的转录过程进行了深入的分析，获得了mRNA和表达的详细数据单。结果表明，在基因组的exon-exon的结合处，92%-94%都经历过选择性剪接。通过选择性剪接，表达出不同的mRNA和蛋白。

 

选择性剪接可能导致表达出的蛋白具有相反的功能，比如说，某个基因经过选择性剪接后表达两种蛋白亚型，一种可激活细胞凋亡路径，而一种则抑制细胞凋亡促进细胞增殖。

 

有趣的是，不同的剪接可能源自不同的组织，在不同的组织中基因的选择性剪接作用发生改变。比如说，某种剪接形式在心脏组织中很常见，但是在脑组织中却很罕见，为了适应不同组织的不同功能，基因的表达通过选择性剪接来调控。甚至，在癌细胞中也存在选择性剪接，这些选择性剪接异于正常细胞的选择性剪接。

 

最终研究者得出结论，选择性剪接、多腺苷酸化等调节过程因组织而异，通过协调调节，表达出适合组织的蛋白。因此，在不同的组织里可能存在一种组织特异的特殊因子，调节组织内的剪接和多腺苷酸化工程。

 

原文摘要：Alternative isoform regulation in human tissue transcriptomes

 

【Abstract】

Through alternative processing of pre-messenger RNAs, individual mammalian genes often produce multiple mRNA and protein isoforms that may have related, distinct or even opposing functions. Here we report an in-depth analysis of 15 diverse human tissue and cell line transcriptomes on the basis of deep sequencing of complementary DNA fragments, yielding a digital inventory of gene and mRNA isoform expression. Analyses in which sequence reads are mapped to exon–exon junctions indicated that 92–94% of human genes undergo alternative splicing, 86% with a minor isoform frequency of 15% or more. Differences in isoform-specific read densities indicated that most alternative splicing and alternative cleavage and polyadenylation events vary between tissues, whereas variation between individuals was approximately twofold to threefold less common. Extreme or 'switch-like' regulation of splicing between tissues was associated with increased sequence conservation in regulatory regions and with generation of full-length open reading frames. Patterns of alternative splicing and alternative cleavage and polyadenylation were strongly correlated across tissues, suggesting coordinated regulation of these processes, and sequence conservation of a subset of known regulatory motifs in both alternative introns and 3' untranslated regions suggested common involvement of specific factors in tissue-level regulation of both splicing and polyadenylation.

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