Histone modifications and a choice of variant: a language that helps the genome express itself

Abstract

Covalent post-translational modifications on histones impact chromatin structure and function. Their misfunction, along with perturbations or mutations in genes that regulate their dynamic status, has been observed in several diseases. Thus, targeting histone modifications represents attractive opportunities for therapeutic intervention and biomarker discovery. The best approach to address this challenge is to paint a comprehensive picture integrating the growing number of modifications on individual residues and their combinatorial association, the corresponding modifying enzymes, and effector proteins that bind modifications. Furthermore, how they are imposed in a distinct manner during the cell cycle and on specific histone variants are important dimensions to consider. Firstly, this report highlights innovative technologies used to characterize histone modifications, and the corresponding enzymes and effector proteins. Secondly, we examine the recent progress made in understanding the dynamics and maintenance of histone modifications on distinct variants. We also discuss their roles as potential carriers of epigenetic information. Finally, we provide examples of initiatives to exploit histone modifications in cancer management, with the potential for new therapeutic opportunities.

Figure 1.. The choreography of histone modifications and variants at the replication fork with their chaperones

Histone chaperones participate in histone deposition during replication and are key candidates to regulate epigenetic inheritance. Parental H3-H4 histones evicted from chromatin are handled by the chaperone ASF1, which also associates with newly synthesized histones [75]. Parental histones and marks are recycled onto daughter strands along with newly synthesized histones with characteristic marks [68,107], the latter deposited by the chaperone CAF-1. Mixing of parental and new histones is rare [108] but may have functional consequences. Importantly, away from the fork, histones are susceptible to turnover, which can alter the modification landscape. Abbreviations: ASF1, anti-silencing function 1; CAF-1, chromatin assembly factor 1; HIRA, histone regulator A; PTM, post-translational modification.

Figure 2.. Histone modification dynamics and maintenance mechanisms

(A) Enzymes having opposing activities maintain steady-state levels of histone marks. (B) A model where the polycomb group protein complex propagates H3K27me3 by binding to the parental histone mark, which recruits the responsible enzyme to methylate neighboring nucleosomes [83]. (C) Histone variant-specific residues can influence how enzymes entertain their substrates, as shown with the ATXR5/6 methyltransferases in plants, where T31 (S31 in mammals) inhibits monomethylation of H3K27 [87]. Abbreviations: ATXR, arabidopsis trithorax-related protein; HAT, histone acetyltransferase; HDAC, histone deacetylase; HMT, histone methyltransferase; (note H is sometimes replaced with K to represent lysine methyltransferase – see [109]); KDM, lysine demethylase; PcG, polycomb group protein.