Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, University of Colorado Health Sciences Center, Aurora, CO 80045, USA.
Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13564-9. doi: 10.1073/pnas.1109475108. Epub 2011 Aug 1.
A chromatin code appears to mark introns and exons with distinct patterns of nucleosome enrichment and histone methylation. We investigated whether a causal relationship exists between splicing and chromatin modification by asking whether splice-site mutations affect the methylation of histone H3K36. Deletions of the 3' splice site in intron 2 or in both introns 1 and 2 of an integrated β-globin reporter gene caused a shift in relative distribution of H3K36 trimethylation away from 5' ends and toward 3' ends. The effects of splice-site mutations correlated with enhanced retention of a U5 snRNP subunit on transcription complexes downstream of the gene. In contrast, a poly(A) site mutation did not affect H3K36 methylation. Similarly, global inhibition of splicing by spliceostatin A caused a rapid repositioning of H3K36me3 away from 5' ends in favor of 3' ends. These results suggest that the cotranscriptional splicing apparatus influences establishment of normal patterns of histone modification.
似乎有一种染色质密码可以用核小体富集和组蛋白甲基化的不同模式来标记内含子和外显子。我们通过询问剪接位点突变是否会影响组蛋白 H3K36 的甲基化，来研究剪接和染色质修饰之间是否存在因果关系。整合的β-珠蛋白报告基因中内含子 2 的 3'剪接位点或内含子 1 和 2 的缺失导致 H3K36 三甲基化的相对分布从 5'端向 3'端转移。剪接位点突变的影响与 U5 snRNP 亚基在基因下游转录复合物上的保留增强相关。相比之下，多聚（A）位点突变不会影响 H3K36 甲基化。同样，剪接抑制剂 spliceostatin A 对剪接的全局抑制导致 H3K36me3 从 5'端快速重新定位到 3'端，有利于 3'端。这些结果表明，共转录剪接装置影响组蛋白修饰的正常模式的建立。
