Alternative transcription exceeds alternative splicing in generating the transcriptome diversity of cerebellar development
Alternative transcription exceeds alternative splicing in generating the transcriptome diversity of cerebellar development
复制标题
DOI：
10.1101/gr.120535.111
复制
发表时间：
2011-08-01
期刊：
影响因子：
7
通讯作者：
Davuluri, Ramana V.
中科院分区：
文献类型：
--
作者：
Pal, Sharmistha;Gupta, Ravi;Davuluri, Ramana V.
尽管我们越来越多地了解到许多哺乳动物基因产生多种转录变体，这些转录变体可能编码功能不同的蛋白质亚型，但各种组织及其发育阶段的转录组却定义不清。识别细胞/组织中的转录组及其调控是破译基因细胞/组织特异性功能的关键。我们利用整合的大规模平行测序和生物信息学方法建立了发育和成年小脑的非编码和蛋白质编码转录物（转录组）、它们的启动子（启动子组）和组蛋白修饰状态（表观基因组）的全基因组清单。该数据由61,525个（12,796个新的）不同mrna组成，由29,589个（4792个新的）启动子转录，对应15,669个蛋白质编码基因和7624个非编码基因。重要的是，我们的研究结果表明，一个基因的转录变异体主要是通过替代转录而不是剪接机制产生的，突出了替代启动子和转录终止是转录组多样性的主要来源。此外，H3K4me3，而不是H3K27me3，定义了替代启动子的使用，我们确定了H3K4me3和H3K27me3在调节转录本表达中的组合作用，包括发育过程中基因的转录本变异。我们观察到H3K4me3和H3K27me3对富含cpg的启动子都有很强的偏向性，并且它们的富集与相应的转录物表达之间存在指数关系。此外，大多数与神经系统疾病相关的基因通过替代启动子表达多个转录本，我们证明了替代启动子在小脑发生的成神经管细胞瘤中的异常使用。本研究中提出的发育和成年小脑的转录组强调了在异构体水平上分析基因调控和功能的重要性。
Despite our growing knowledge that many mammalian genes generate multiple transcript variants that may encode functionally distinct protein isoforms, the transcriptomes of various tissues and their developmental stages are poorly defined. Identifying the transcriptome and its regulation in a cell/tissue is the key to deciphering the cell/tissue-specific functions of a gene. We built a genome-wide inventory of noncoding and protein-coding transcripts (transcriptomes), their promoters (promoteromes) and histone modification states (epigenomes) for developing, and adult cerebella using integrative massive-parallel sequencing and bioinformatics approach. The data consists of 61,525 (12,796 novel) distinct mRNAs transcribed by 29,589 (4792 novel) promoters corresponding to 15,669 protein-coding and 7624 noncoding genes. Importantly, our results show that the transcript variants from a gene are predominantly generated using alternative transcriptional rather than splicing mechanisms, highlighting alternative promoters and transcriptional terminations as major sources of transcriptome diversity. Moreover, H3K4me3, and not H3K27me3, defined the use of alternative promoters, and we identified a combinatorial role of H3K4me3 and H3K27me3 in regulating the expression of transcripts, including transcript variants of a gene during development. We observed a strong bias of both H3K4me3 and H3K27me3 for CpG-rich promoters and an exponential relationship between their enrichment and corresponding transcript expression. Furthermore, the majority of genes associated with neurological diseases expressed multiple transcripts through alternative promoters, and we demonstrated aberrant use of alternative promoters in medulloblastoma, cancer arising in the cerebellum. The transcriptomes of developing and adult cerebella presented in this study emphasize the importance of analyzing gene regulation and function at the isoform level.