Ras-induced changes in H3K27me3 occur after those in transcriptional activity.
Ras-induced changes in H3K27me3 occur after those in transcriptional activity.
复制标题
DOI：
10.1371/journal.pgen.1003698
复制
发表时间：
2013-08
期刊：
影响因子：
4.5
通讯作者：
Nakayama K
中科院分区：
文献类型：
--
作者：
Hosogane M;Funayama R;Nishida Y;Nagashima T;Nakayama K
致癌信号通路部分通过染色质的表观遗传修饰调控基因表达，包括DNA甲基化和组蛋白修饰。赖氨酸-27位点组蛋白H3 （H3K27）的三甲基化与转录抑制相关，受一种致癌形式的小GTPase Ras调控。尽管三甲基化H3K27 （H3K27me3）的积累与转录调节有关，但仍不清楚ras诱导的H3K27me3的变化是转录活性变化的触发因素还是结果。我们现在研究了H3K27三甲基化和Ras转录调控之间的关系。在小鼠NIH 3T3细胞中表达致癌Ras后，对H3K27me3在不同时期的分布和转录进行全基因组分析，鉴定出115个基因体上的H3K27me3水平和转录均受Ras调控的基因。同样，196个基因显示ras诱导的转录和转录起始位点周围区域H3K27me3水平的变化。在全基因组水平上，ras诱导的转录变化发生在H3K27me3之前，这一发现通过对单个基因的分析得到了验证。在激活Ras信号之前或之后，H3K27me3的缺失并不影响这些基因的转录调节。此外，考虑到H3K27me3的富集依赖于Ras信号，在该信号失活后，H3K27me3的富集和转录抑制都无法维持。出乎意料的是，我们检测到来自H3K27me3水平受Ras调控的基因间区域的未注释转录本，转录本丰度的变化再次领先于H3K27me3。因此，我们的研究结果表明，基因体内或转录起始位点周围区域的H3K27me3水平的变化不是转录活性变化的触发因素，而是转录活性变化的结果。赖氨酸-27位点组蛋白H3 （H3K27）的三甲基化与基因表达的沉默有关。这种修饰的异常被认为有助于肿瘤抑制基因的表观遗传沉默，并被认为是癌症的标志。然而，尚不清楚三甲基化H3K27 （H3K27me3）的产生是基因沉默的原因还是结果。为了解决这个问题，我们研究了H3K27me3水平变化的时间过程，以及由Ras蛋白的致癌形式诱导的基因转录变化的时间过程，Ras蛋白是人类癌症中最常见的突变基因之一。我们发现H3K27me3的数量在全基因组水平和单个基因水平上都与转录活性呈负相关。然而，我们也发现ras诱导的H3K27me3水平的变化发生在转录活性的变化之后。因此，我们的研究结果表明，H3K27me3丰度的变化是转录调控的结果而不是原因，并且他们表明癌蛋白驱动的基因转录变化可以改变癌细胞中组蛋白修饰的模式。
Oncogenic signaling pathways regulate gene expression in part through epigenetic modification of chromatin including DNA methylation and histone modification. Trimethylation of histone H3 at lysine-27 (H3K27), which correlates with transcriptional repression, is regulated by an oncogenic form of the small GTPase Ras. Although accumulation of trimethylated H3K27 (H3K27me3) has been implicated in transcriptional regulation, it remains unclear whether Ras-induced changes in H3K27me3 are a trigger for or a consequence of changes in transcriptional activity. We have now examined the relation between H3K27 trimethylation and transcriptional regulation by Ras. Genome-wide analysis of H3K27me3 distribution and transcription at various times after expression of oncogenic Ras in mouse NIH 3T3 cells identified 115 genes for which H3K27me3 level at the gene body and transcription were both regulated by Ras. Similarly, 196 genes showed Ras-induced changes in transcription and H3K27me3 level in the region around the transcription start site. The Ras-induced changes in transcription occurred before those in H3K27me3 at the genome-wide level, a finding that was validated by analysis of individual genes. Depletion of H3K27me3 either before or after activation of Ras signaling did not affect the transcriptional regulation of these genes. Furthermore, given that H3K27me3 enrichment was dependent on Ras signaling, neither it nor transcriptional repression was maintained after inactivation of such signaling. Unexpectedly, we detected unannotated transcripts derived from intergenic regions at which the H3K27me3 level is regulated by Ras, with the changes in transcript abundance again preceding those in H3K27me3. Our results thus indicate that changes in H3K27me3 level in the gene body or in the region around the transcription start site are not a trigger for, but rather a consequence of, changes in transcriptional activity. Trimethylation of histone H3 at lysine-27 (H3K27) has been associated with silencing of gene expression. Abnormalities of this modification are thought to contribute to the epigenetic silencing of tumor suppressor genes and are regarded as a hallmark of cancer. It has remained unclear, however, whether the production of trimethylated H3K27 (H3K27me3) is the cause or the consequence of gene silencing. To address this issue, we examined the time courses of changes in H3K27me3 level and those in gene transcription induced by an oncogenic form of the Ras protein, the gene for which is one of the most frequently mutated in human cancer. We found that the amount of H3K27me3 was inversely related to transcriptional activity both at the genome-wide level and at the level of individual genes. However, we also found that the Ras-induced changes in H3K27me3 level occurred after those in transcriptional activity. Our results thus demonstrate that changes in H3K27me3 abundance are a consequence rather than a cause of transcriptional regulation, and they suggest that oncoprotein-driven changes in gene transcription can alter the pattern of histone modification in cancer cells.
登录
查看更多内容
影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
10.5
作者：
Barradas, Marta;Anderton, Emma;Gil, Jesus
通讯作者：
Gil, Jesus
影响因子：
10.5
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
Helin, Kristian
影响因子：
4.5
作者：
Kaneda A;Fujita T;Anai M;Yamamoto S;Nagae G;Morikawa M;Tsuji S;Oshima M;Miyazono K;Aburatani H
通讯作者：
Aburatani H
影响因子：
21.3
作者：
Hansen, Klaus H.;Bracken, Adrian P.;Helin, Kristian
通讯作者：
Helin, Kristian