Ras-induced changes in H3K27me3 occur after those in transcriptional activity

Autor: Masaki Hosogane, Takeshi Nagashima, Keiko Nakayama, Ryo Funayama, Yuichiro Nishida
Rok vydání: 2012
Předmět:
Zdroj: PLoS Genetics
PLoS Genetics, Vol 9, Iss 8, p e1003698 (2013)
ISSN: 1553-7404
Popis: 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.
Author Summary 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.
Databáze: OpenAIRE
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