Accumulation of H3K27me3 Is Triggered by Transcriptional Repression. Mus musculus

Histone H3 trimethylated at lysine-27 (H3K27me3) is associated with transcriptional repression, and its abundance in chromatin is frequently altered in cancer. However, it has remained unclear whether the accumulation of H3K27me3 induces transcriptional repression or vice versa. We previously showed that down-regulation of transcription by oncogenic Ras signaling precedes up-regulation of H3K27me3 level. Here we show that transcriptional repression induced by deletion of the transcription start site of a gene is sufficient to increase H3K27me3 content in the gene body. We further found that histone deacetylation mediates gene silencing induced by Ras signaling. Inhibition of deacetylation thus interfered with both Ras-induced gene silencing and subsequent H3K27me3 accumulation. The H3K27me3 level increased gradually after Ras activation, requiring at least 35 days to achieve saturation. Such maximal accumulation of H3K27me3 was reversed by forced induction of transcription with the dCas9-activator system. Our results thus indicate that changes in H3K27me3 level are triggered by changes in transcriptional activity itself.