A correlation with exon expression approach to identify cis-regulatory elements for tissue-specific alternative splicing.
A correlation with exon expression approach to identify cis-regulatory elements for tissue-specific alternative splicing.
复制标题
与外显子表达方法的相关性，以识别组织特异性替代剪接的顺式调节元件。
DOI：
10.1093/nar/gkm485
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发表时间：
2007
影响因子：
14.9
通讯作者：
Conboy, John G
中科院分区：
文献类型：
--
作者：
Das, Debopriya;Clark, Tyson A;Schweitzer, Anthony;Yamamoto, Miki;Marr, Henry;Arribere, Josh;Minovitsky, Simon;Poliakov, Alexander;Dubchak, Inna;Blume, John E;Conboy, John G
基序发生与基因表达强度的相关性是阐明转录顺式调控逻辑的有效策略。在这里，我们证明了这种方法也可以识别选择性前mrna剪接的顺式调控元件。利用人类外显子微阵列的数据，我们鉴定出56个盒式外显子在肌肉中比在其他正常成人组织中表现出更高的转录标准化表达。然后分析这些外显子两侧的内含子序列，以确定肌肉特异性选择性剪接的候选调节基序。利用RNA词和退化权矩阵的线性回归和线性样条分析了基序参数与基因归一化外显子表达水平的相关性。我们的无偏分析揭示了肌肉特异性剪接的多个候选调控基序，其中许多在脊椎动物基因组中是系统发育保守的。最突出的下游基序是Fox1-和celf相关剪接因子的结合位点，以及分支点样元件acaac；与ptb结合位点相似的富嘧啶元素在上游内含子中最为显著。有趣的是，我们的系统研究表明，缺乏在近端短内含子区域占主导地位的新型肌肉特异性元件。我们提出Fox和CELF蛋白在执行肌肉特异性选择性剪接程序中发挥主要作用，促进对肌肉细胞功能至关重要的细胞骨架蛋白独特同种异构体的表达。
Correlation of motif occurrences with gene expression intensity is an effective strategy for elucidating transcriptional cis-regulatory logic. Here we demonstrate that this approach can also identify cis-regulatory elements for alternative pre-mRNA splicing. Using data from a human exon microarray, we identified 56 cassette exons that exhibited higher transcript-normalized expression in muscle than in other normal adult tissues. Intron sequences flanking these exons were then analyzed to identify candidate regulatory motifs for muscle-specific alternative splicing. Correlation of motif parameters with gene-normalized exon expression levels was examined using linear regression and linear splines on RNA words and degenerate weight matrices, respectively. Our unbiased analysis uncovered multiple candidate regulatory motifs for muscle-specific splicing, many of which are phylogenetically conserved among vertebrate genomes. The most prominent downstream motifs were binding sites for Fox1- and CELF-related splicing factors, and a branchpoint-like element acuaac; pyrimidine-rich elements resembling PTB-binding sites were most significant in upstream introns. Intriguingly, our systematic study indicates a paucity of novel muscle-specific elements that are dominant in short proximal intronic regions. We propose that Fox and CELF proteins play major roles in enforcing the muscle-specific alternative splicing program, facilitating expression of unique isoforms of cytoskeletal proteins critical to muscle cell function.