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 under-developed. 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.An important mechanism for regulating chromatin involves the reversible covalent modification of histones by chemical moieties such as methyl and acetyl groups. These different chemical 'marks' on histones are linked to discrete chromatin states and regulate the accessibility of DNA to trans-acting factors that mediate a wide variety of chromatintemplated processes such as transcription, DNA repair and DNA replication 1 . Chemically, lysine methylation entails the addition of one, two or three methyl groups to the ε-nitrogen of a lysine side chain, forming mono-, di-and trimethylated derivatives (referred to here as Kme1, Kme2, and Kme3, respectively; Fig. 1a). This reaction, while only subtly changing the primary structure of the modified polypeptide, greatly increases the information encoded within the molecule, a feature highlighted by the unique activities frequently coupled to the specific extent of methylation. Methylation of lysines on histone and non-histone proteins is generated by protein lysine methyltransferases (KMTs; referred to as 'writers') and removed by protein lysine demethylases (KDMs; referred to as 'erasers') (Fig. 1a). In the human genome, there are predicted to be over 100 KMTs, and mass spectrometry-based studies suggest that more than 1,000 proteins in the human proteome harbor lysine methylation 2-4 . Lysine methylation was first described in 1959 on a bacterial flagellar protein 5 and soon thereafter identified on histone proteins 6 . Indeed, the core histones contain numerous Reprints and permissions information is available at www.nature.com/reprints.

Histone demethylase Lsd1 is required for the differentiation of neural cells in the cnidarianNematostella vectensis

“…In particular, it is now clear that chromatin modifiers are not static, permissive actors in the process of cell differentiation but rather play an active role (4). Indeed, chromatin modifiers such as those involved in histone lysine methylation and demethylation often play cell or tissue specific roles (5,6). Such chromatin modifiers can themselves be regulated, at the level of expression, splicing, localization and activity in order to allow for differential functions in different cells or tissues.…”

NSD1 in erythroid differentiation and leukemogenesis

“…This process is conducted by multiple histone lysine methyltransferase (KMT) enzymes and results in either activation or repression of gene expression. 1 Recurrent genetic alterations in KMT leading to aberrant histone modifications are frequently detected in acute myeloid leukemia (AML) and have been shown to act as drivers of the disease. 2 The nuclear receptor-binding SET domain protein 1 (NSD1) has been characterized as a mono-and dimethyltransferase of histone H3K36.…”

Epigenetic gene-expression links heart failure to memory impairment

“…Moreover, although Vorinostat increases H3K4me3, this indirect effect is most likely mediated by 23 increased histone acetylation that generally promotes euchromatin formation. In line with this previous 24 findings show that Kmts act in concert with histone-acetyltransferases (Kerimoglu et al, 2013) 25 (Kerimoglu et al, 2017) (Husmann & Gozani, 2019). Nevertheless, in the future, it will be important to 26 investigate whether therapeutic approaches that target more directly H3K4me3 are even more efficient to 27 reinstate memory function in response to HF.…”