Abstract
SIGNIFICANCE: Methylation of histone H3 on lysine 9 and 27 (H3K9 and H3K27) are two epigenetic modifications that have been linked to several crucial biological processes, among which are transcriptional silencing and cell differentiation. RECENT ADVANCES: Deposition of these marks is catalyzed by H3K9 lysine methyltransferases (KMTs) and polycomb repressive complex 2, respectively. Increasing evidence is emerging in favor of a functional crosstalk between these two major KMT families. CRITICAL ISSUES: Here, we review the current knowledge on the mechanisms of action and function of these enzymes, with particular emphasis on their interplay in the regulation of chromatin states and biological processes. We outline their crucial roles played in tissue homeostasis, by controlling the fate of embryonic and tissue-specific stem cells, highlighting how their deregulation is often linked to the emergence of a number of malignancies and neurological disorders. FUTURE DIRECTIONS: Histone methyltransferases are starting to be tested as drug targets. A new generation of highly selective chemical inhibitors is starting to emerge. These hold great promise for a rapid translation of targeting epigenetic drugs into clinical practice for a number of aggressive cancers and neurological disorders.