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Published on: January 26, 2018
Ras-induced changes in H3K27me3 occur after those in transcriptional activity
Masaki Hosogane1, Ryo Funayama, Yuichiro Nishida
1Department of Cell Proliferation, United Center for Advanced Research and Translational Medicine, Graduate School of Medicine, Tohoku University, Seiryo-machi, Aoba-ku, Sendai, Japan.
Abstract:
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.
Insights
Oncogenic Ras signaling alters gene expression. This study shows that changes in histone H3 lysine-27 trimethylation (H3K27me3) follow, rather than cause, Ras-induced transcriptional changes, including in unannotated regions.
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Biology
Background:
- Oncogenic signaling pathways, such as Ras, influence gene expression through epigenetic modifications like DNA methylation and histone modification.
- Histone H3 trimethylation at lysine-27 (H3K27me3) is associated with transcriptional repression and is regulated by oncogenic Ras.
- The precise role of H3K27me3 accumulation in Ras-induced transcriptional regulation—whether as a cause or effect—remains unclear.
Purpose of the Study:
- To investigate the relationship between Ras-induced changes in H3K27me3 and transcriptional activity.
- To determine if H3K27me3 modifications precede or follow transcriptional changes mediated by oncogenic Ras.
- To explore the impact of H3K27me3 depletion on Ras-driven gene expression.
Main Methods:
- Genome-wide analysis of H3K27me3 distribution and gene transcription in mouse NIH 3T3 cells following oncogenic Ras expression.
- Time-course analysis to compare the timing of transcriptional changes versus H3K27me3 modifications.
- Experimental depletion of H3K27me3 to assess its necessity for Ras-induced transcriptional regulation.
- Analysis of unannotated transcripts in intergenic regions.
Main Results:
- Ras-induced transcriptional changes were observed genome-wide before corresponding changes in H3K27me3 levels.
- 115 genes showed coordinated regulation of H3K27me3 in the gene body and transcription by Ras.
- 196 genes exhibited Ras-induced changes in transcription and H3K27me3 near the transcription start site.
- Depletion of H3K27me3 did not alter Ras-mediated transcriptional regulation.
- Ras-regulated H3K27me3 and transcriptional repression were not sustained upon Ras signaling inactivation.
- Unannotated transcripts from intergenic regions also showed Ras-dependent H3K27me3 regulation, with transcript changes preceding H3K27me3 alterations.
Conclusions:
- Ras-induced alterations in H3K27me3 are a consequence, not a trigger, of changes in transcriptional activity.
- H3K27me3 modifications in gene bodies or near transcription start sites do not initiate Ras-driven transcriptional repression.
- Epigenetic changes, specifically H3K27me3, dynamically respond to oncogenic signaling rather than driving it.
- Ras signaling influences transcription and associated epigenetic marks in both annotated and unannotated genomic regions.
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