Evidence for Transcript Networks Composed of Chimeric RNAs in Human Cells

The classic organization of a gene structure has followed the Jacob and Monod bacterial gene model proposed more than 50 years ago. Since then, empirical determinations of the complexity of the transcriptomes found in yeast to human has blurred the definition and physical boundaries of genes. Using multiple analysis approaches we have characterized individual gene boundaries mapping on human chromosomes 21 and 22. Analyses of the locations of the 5′ and 3′ transcriptional termini of 492 protein coding genes revealed that for 85% of these genes the boundaries extend beyond the current annotated termini, most often connecting with exons of transcripts from other well annotated genes. The biological and evolutionary importance of these chimeric transcripts is underscored by (1) the non-random interconnections of genes involved, (2) the greater phylogenetic depth of the genes involved in many chimeric interactions, (3) the coordination of the expression of connected genes and (4) the close in vivo and three dimensional proximity of the genomic regions being transcribed and contributing to parts of the chimeric RNAs. The non-random nature of the connection of the genes involved suggest that chimeric transcripts should not be studied in isolation, but together, as an RNA network.基因结构的经典组织形式一直沿用五十余年前提出的雅各布与莫诺（Jacob and Monod）细菌基因模型。自那时起，对从酵母到人类各类物种中转录组（transcriptome）复杂度的实证测定，已然模糊了基因的定义及其物理边界。本研究采用多种分析方法，对人类21号与22号染色体上的单个基因边界定位进行了系统表征。针对492个蛋白编码基因的5′端与3′端转录末端位点的分析显示，其中85%的基因边界均超出了当前的注释末端位点，且大多与其他已注释完善基因的转录本外显子（exon）相连。这些嵌合转录本（chimeric transcript）的生物学与进化重要性得到了以下四点的佐证：其一，所涉及基因间存在非随机的相互连接；其二，参与诸多嵌合相互作用的基因具有更深的系统发育深度；其三，相连基因的表达具有协同性；其四，被转录并参与构成嵌合RNA（chimeric RNA）片段的基因组区域，在体内（in vivo）及三维空间上彼此紧密邻近。所涉及基因连接的非随机特性表明，嵌合转录本不应被孤立研究，而应作为RNA网络（RNA network）整体开展联合分析。