Histone lysine methyltransferases in biology and disease

Abstract

The precise temporal and spatial coordination of histone lysine methylation dynamics across the epigenome regulates virtually all DNA-templated processes. A large number of histone lysine methyltransferase (KMT) enzymes catalyze the various lysine methylation events decorating the core histone proteins. Mutations, genetic translocations and altered gene expression involving these KMTs are frequently observed in cancer, developmental disorders and other pathologies. Therapeutic compounds targeting specific KMTs are currently being tested in the clinic, although overall drug discovery in the field is relatively underdeveloped. Here we review the biochemical and biological activities of histone KMTs and their connections to human diseases, focusing on cancer. We also discuss the scientific and clinical challenges and opportunities in studying KMTs.

Fig. 1 |. Main sites of lysine methylation on mammalian histones and chromatin functions.

a, Chemical structures of methylated derivatives of lysine. Lysine residues can be monomethylated, dimethylated or trimethylated. b,c, Canonical (b) and non-canonical (c) lysine methylation marks on core nucleosomal histone H3 and H4 and their basic functions. Numbers adjacent to ‘K’ indicate the positions of the methylated lysines on histone H3 or histone H4. DNA is shown as black lines wrapped around blue histones. Key (right), chromatin-related functions associated with the methylation at left.

Fig. 2 |. Histone KMTs in the human proteome.

a, Human histone KMTs categorized by their established substrate specificity. b, Top: Examples of additional histone KMT activities. Bottom: Methylation is also detected at the non-canonical H3K18, K23, K56 and K64 sites, but the enzymes catalyzing these events are not known. c, Top two rows: generation of H3K36 trimethylation is not dependent on existing dimethylation. Bottom row: generation of H4K20me2 and H4K20me3 is dependent upon SETD8-generated H4K20me1.

Fig. 3 |. Spectrum of cancers associated with H3K36 methyltransferases.

The potential tumor-suppressive functions listed are informed by the identification of recurrent deletions, frameshifts, or truncating or damaging missense mutations, and by biological studies, including mouse models. Potential oncogenic functions are informed by overexpression, focal amplifications, gain of function or identification of a fusion oncogene, and by biological studies, including mouse models. CNS, central nervous system; HSTL, hepatosplenic T cell lymphoma; EATL-II, enteropathy-associated T cell lymphoma, type II; LSCC, lung squamous-cell carcinoma.

Fig. 4 |. Model for crosstalk between methylation at H3K27 and H3K36 in oncogenic programming.

Deregulation of the dynamic interplay between methylation at H3K27 and that at H3K36 leads to pathological transcriptional activation or repression and thereby promotes oncogenic reprogramming.