Histone H3 lysine 27 trimethylation mark (H3K27me3) (H3K27me3)

Histone H3 lysine 27 trimethylation (H3K27me3) is a critical epigenetic modification associated with transcriptional repression and the formation of facultative heterochromatin (Margueron & Reinberg, 2011, Nature). This mark is primarily deposited by the Polycomb Repressive Complex 2 (PRC2), with EZH2 serving as the catalytic subunit, and is removed by the demethylases KDM6A (UTX) and KDM6B (JMJD3) (Ferrari et al., 2014, Molecular Cell). In healthy cells, H3K27me3 plays a vital role in regulating developmental genes, maintaining stem cell identity, and mediating X-chromosome inactivation. Dysregulation of H3K27me3 is a hallmark of various cancers; for instance, gain-of-function mutations in EZH2 lead to H3K27me3 hypermethylation and silencing of tumor suppressor genes in B-cell lymphomas (Morin et al., 2010, Nature Genetics). Conversely, the loss of this mark, often due to H3K27M "oncohistone" mutations, is a defining feature of certain pediatric high-grade gliomas (Bender et al., 2013, Cancer Cell). Therapeutic strategies focus on modulating H3K27me3 levels using small molecule inhibitors of EZH2, such as Tazemetostat, which has been approved for treating epithelioid sarcoma and follicular lymphoma (FDA, 2020).

Other names

H3K27me3Trimethyl-Histone H3 (Lys27)H3K27 trimethylationLysine 27 trimethylation of histone H3

Therapeutic modulation of H3K27me3 is primarily achieved through the inhibition of EZH2 (Enhancer of zeste homolog 2), the catalytic subunit of the PRC2 complex responsible for methylating H3K27. By inhibiting EZH2, drugs reduce the levels of H3K27me3, thereby reversing the silencing of tumor suppressor genes (FDA, 2020; Morin et al., 2010, Nature Genetics).