VII. Are lymphomas driven by epigenetic lesions?

Epigenetic regulation of gene expression is a process driven by dynamic changes in chromatin architecture carried out by histone-modifying enzymes. In eukaryotic organisms, chromatin organization allows tight packaging of the genomewhile still allowing access to transcriptional machinery. The basic unit of chromatin is the nucleosome, which consists of DNA wrapped around an octamer of histone proteins. Histone tails are post-translationally modified by covalent modifications such as methylation or acetylation that occur at lysine and arginine residues. These histone modifications, or ‘marks’, result in changes to chromatin structure and serve as a histone code that directs the ordered recruitment of effector proteins that control gene transcription, replication and DNA repair [1]. A number of enzymes are responsible for establishing the histone code, by functioning as writers, readers and erasers of histone marks. These epigenetic modifiers are directed by transcription factors to histones located within DNA regulatory elements, including enhancers and promoters, allowing gene expression to be turned on or off. Histone marks associated with transcriptional activation include histone 3 lysine 4 methylation (H3K4me) and H3 lysine 27 acetylation (H3K27ac), whereas H3 lysine 27 methylation (H3K27me) is generally linked to repression. The functional state of enhancer regions that control cell context-specific gene expression can be defined from the chromatin standpoint as being in an active (H3K4me1/2 and H3K27ac), or poised (H3K4me1/2 and H3K27me3) configuration. Specific patterning of histone marks is context dependent and can change rapidly in response to external stimuli, providing a layer of epigenetic control to regulate cell fate and function decisions. Somatic mutation of histone-modifying enzymes is now recognized as a hallmark of certain forms of B-cell lymphomas. Here, we will focus on some of the more frequently affected histone-modifying enzymes in B-cell lymphomas and their potential mechanisms of action.