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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.
Highlights
Epigenetic modification of chromatin is a key mechanism for regulation of gene expression [1,2]
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
Summary
Epigenetic modification of chromatin is a key mechanism for regulation of gene expression [1,2]. Chromatin immunoprecipitation (ChIP) followed by deep sequencing (ChIP-seq) as well as chip-based ChIP have been applied to map precisely the distribution of H3K27me across the entire genome. These approaches have been adopted to elucidate the relation between the distribution of H3K27me and transcriptional activity. A broad enrichment of H3K27me, known as a blanket-type pattern or broad local enrichment (BLOC), has been detected over larger genomic regions including the TSS [13,14,15,16,17] This pattern of modification has been associated with individual repressed genes and with repressed gene clusters, and it is frequently observed in differentiated cells. Both of these enrichment patterns are highly variable among cell types [18,19], indicating that the distribution of H3K27me is regulated in a manner dependent on the cellular and developmental context
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