Understanding histone H3 lysine 36 methylation and its deregulation in disease

Abstract

Methylation of histone H3 lysine 36 (H3K36) plays crucial roles in the partitioning of chromatin to distinctive domains and the regulation of a wide range of biological processes. Trimethylation of H3K36 (H3K36me3) demarcates body regions of the actively transcribed genes, providing signals for modulating transcription fidelity, mRNA splicing and DNA damage repair; and di-methylation of H3K36 (H3K36me2) spreads out within large intragenic regions, regulating distribution of histone H3 lysine 27 trimethylation (H3K27me3) and possibly DNA methylation. These H3K36 methylation-mediated events are biologically crucial and controlled by different classes of proteins responsible for either 'writing', 'reading' or 'erasing' of H3K36 methylation marks. Deregulation of H3K36 methylation and related regulatory factors leads to pathogenesis of disease such as developmental syndrome and cancer. Additionally, recurrent mutations of H3K36 and surrounding histone residues are detected in human tumors, further highlighting the importance of H3K36 in biology and medicine. This review will elaborate on current advances in understanding H3K36 methylation and related molecular players during various chromatin-templated cellular processes, their crosstalks with other chromatin factors, as well as their deregulations in the diseased contexts.

Keywords: Cancer; Chromatin; DNA damage repair; DNA methylation; Demethylase; Epigenetics; Gene transcription; H3K27me3; H3K36 methylation; H3K36me2; H3K36me3; Histone modification; Methyltransferase; Splicing.

Fig. 1

Structures of the H3K36 methylation-specific ‘reader’ domains, as exemplified by a the chromodomain of MRG15 (PDB: 2F5K), b the PWWP domain of DNMT3B (PDB: 5CIU) and c the Tudor domain of PHF19 (PDB: 4BD3). The H3K36me3-engaging residues are labeled in each panel, with the histone peptide shown in gold

Fig. 2

Suppression of cryptic intragenic transcripts by H3K36me3. Both the yeast Set2 and the mammalian SETD2 bind the elongating RNAPII and decorate the gene body regions with H3K36me3. In yeast (a), the H3K36me3 recruits the Rpd3S histone deacetylase complex to deacetylate the transcribed body regions to suppress spurious intragenic transcripts. Unlike yeast, the mammalian cells (b) employ different H3K36me3 ‘readers’, a de novo methyltransferase DNMT3B and the MRG15–KDM5B complex, to methylate DNA and remove H3K4me3, respectively, thus leading to inactivation of intragenic promoters; as well, SETD2 recruits the FACT complex to facilitate nucleosome structure recovery after RNAPII passage, thus preventing RNAPII entry into the intragenic promoters

Fig. 3

Crosstalk of H3K36 methylation with H3K27 methylation and DNA methylation. In the intergenic regions, the NSD1-catalyzed H3K36me2 prevents spreading of the PRC2-catalyzed H3K27me3, and loss of NSD1 causes genome-wide loss of H3K36me2 and DNA methylation, as well as concomitant gain of H3K27me3. Intrusion and spreading of the PRC2-catalyzed H3K27me3 into the active gene bodies are assisted by PHF1 or PHF19, which mediates ‘reading’ of H3K36me3. Furthermore, CpG island elements recruit KDM2A to remove H3K36me2

Fig. 4

H3K36 methylation-mediated promotion of DNA damage repair via both DNA mismatch repair (MMR) and double-strand break (DSB) pathways. Specifically, the SETD2-catalyzed H3K36me3 is recognized by the mismatch sensor hMutSa, thereby promoting MMR during active gene transcription. In response to DSB, Metnase is activated to catalyze H3K36me2 near the DSB site, which in turn recruits the Ku70–NBS1 complex for damage repair via NHEJ. Unlike H3K36me2, the SETD2-catalyzed H3K36me3 also favors HR repair of DSB by orchestrating assembly of an H3K36me3 ‘reader’ complex, LEDGF–CtlP

Fig. 5

H3K36me3 modulates alternative splicing of mRNA via its ‘readers’ and recruited splicing machineries. Recognition of H3K36me3 by MRG15 recruits PTB, leading to enhanced splicing of alternative exons, whereas binding of the LEDGF–SRSF1 complex to H3K36me3 facilitates inclusion of alternative exons. Further, ZMYND11 specifically ‘reads’ H3.3K36me3 and opposes the intron-splicing activity of EFTUD2, thus resulting in intron retention