Polycomb-Dependent H3K27me1 and H3K27me2 Regulate Active Transcription and Enhancer Fidelity

Abstract

H3K27me3 is deposited at promoters by the preferential association of Polycomb repressive complex 2 (PRC2) with CpG-rich DNA elements regulating development by repressing gene transcription. H3K27 is also present in mono- and dimethylated states; however, the functional roles of H3K27me1 and H3K27me2 deposition remain poorly characterized. Here, we show that PRC2 activity is not only associated with H3K27me3 but also regulates all forms of H3K27 methylation in a spatially defined manner, contributing to different genomic functions in mouse embryonic stem cells. H3K27me1 accumulates within transcribed genes, promotes transcription, and is regulated by Setd2-dependent H3K36me3 deposition. Contrarily, H3K27me2 is present on approximately 70% of total histone H3 and is distributed in large chromatin domains, exerting protective functions by preventing firing of non-cell-type-specific enhancers. Considering that only 5%-10% of deregulated genes in PRC2-deficient cells are direct H3K27me3 targets, our data support an active role for all H3K27 methylated forms in regulating transcription and determining cell identity.

Genome-wide activities of Polycomb complexes control pervasive transcription

“…In particular, PRC2 produces a widespread and remarkably high level of H3K27me2 in flies and mammals that accounts for 45%-70% of all histone H3, while H3K27me3 constitutes 5%-10% (Peters et al 2003;Ebert et al 2004;Jung et al 2010;Voigt et al 2012;Ferrari et al 2014). Quantitatively, H3K27 dimethylation is therefore the major function of the PRC2 complex, but its effects have gone largely unexplored.…”

Functional Crosstalk Between Lysine Methyltransferases on Histone Substrates: The Case of G9A/GLP and Polycomb Repressive Complex 2

“…Ezh1, the Ezh2 homolog, has been suggested to play such a role (135) but its activity toward H3K27 remains controversial (81). Although the evidence that H3K27me1 levels remain unaffected after PRC2 disruption in vivo (23) suggests the existence of a H3K27 monomethyltransferase other than a known PRC2 component (92), a recent report has directly implicated PRC2 in the genomic distribution of H3K27me1 (43). This work demonstrates that PRC2 controls all forms of H3K27 methylation, including H3K27me1, and shows that H3K27me2 is actually the main activity of PRC2 (43).…”

“…Although the evidence that H3K27me1 levels remain unaffected after PRC2 disruption in vivo (23) suggests the existence of a H3K27 monomethyltransferase other than a known PRC2 component (92), a recent report has directly implicated PRC2 in the genomic distribution of H3K27me1 (43). This work demonstrates that PRC2 controls all forms of H3K27 methylation, including H3K27me1, and shows that H3K27me2 is actually the main activity of PRC2 (43). Intriguingly, genomic localization of the different H3K27 methylations (mono-di-and tri-) seems to be mutually exclusive and regulates different genomic functions.…”

“…Intriguingly, genomic localization of the different H3K27 methylations (mono-di-and tri-) seems to be mutually exclusive and regulates different genomic functions. While H3K27me3 is mostly associated to CpG-rich promoters (64,85) and involved in cell-specific maintenance of epigenetic silencing (87), H3K27me2 has been rather suggested to exert a protective function by inhibiting the firing of non-cell type-specific enhancers (43). In contrast, H3K27me1 has been shown to accumulate, in a PRC2-dependent manner, in the bodies of actively transcribed genes (11,43), thereby promoting gene transcription (43).…”

“…While H3K27me3 is mostly associated to CpG-rich promoters (64,85) and involved in cell-specific maintenance of epigenetic silencing (87), H3K27me2 has been rather suggested to exert a protective function by inhibiting the firing of non-cell type-specific enhancers (43). In contrast, H3K27me1 has been shown to accumulate, in a PRC2-dependent manner, in the bodies of actively transcribed genes (11,43), thereby promoting gene transcription (43). Intriguingly, Ezh1 has been recently suggested to interact with ribonucleic acid (RNA) polymerase II and promote RNA elongation, thus inducing transcriptional activation of muscle-specific genes in differentiating myoblasts (90).…”