Structural landscape of H3K27me3 recognition by protein domains and their potential for inhibition.

A fraction of the eukaryotic genome is transcriptionally silenced in the form of facultative heterochromatin, characterized by the histone H3 lysine 27 tri-methyl (H3K27me3) modification. The cell-specific and dynamic nature of H3K27me3-marked chromatin is centrally regulated by the catalytic function of the polycomb repressive complex 2 (PRC2) that deposits it; however, the mark can also be removed to activate transcription by the demethylases UTX and JMJD3. An important regulatory mechanism of facultative heterochromatin is the molecular recognition of the H3K27me3 modification by a group of small globular proteins termed readers. Across multiple organisms, the readers of H3K27me3 that have been structurally characterized bound to H3 peptides are restricted to the chromodomain, BAH, Tudor, and the WD40 EED. Here, we review the structural diversity of the protein domains that bind to H3K27me3 and highlight the different binding preferences beyond the recognition of the K27me3 moiety. Furthermore, we note recent findings that suggest the nucleosome structure can enhance the specificity of readers for H3K27me3, adding a new layer of regulation. Finally, we discuss the prevalence of misregulation of H3K27me3 and its cognate proteins in human diseases, and the potential of the latter for therapeutic intervention. Remarkably, almost all the H3K27me3-related proteins are found misregulated in malignances that affect the brain and the nervous system, along with a strong prevalence in cancers of other tissues. Pharmacological efforts to target these pathways include peptide-based inhibitors and small molecules that can block recognition of H3K27me3 by allosteric, complex-disruptive, or degradation-inducing mechanisms of inhibition.