The methylation of histone H3 at lysine 36 (H3K36me) is essential for maintaining genomic stability. Indeed, this methylation mark is essential for proper transcription, recombination, and DNA damage response. Loss- and gain-of-function mutations in H3K36 methyltransferases are closely linked to human developmental disorders and various cancers. Structural analyses suggest that nucleosomal components such as the linker DNA and a hydrophobic patch constituted by histone H2A and H3 are likely determinants of H3K36 methylation in addition to the histone H3 tail, which encompasses H3K36 and the catalytic SET domain. Interaction of H3K36 methyltransferases with the nucleosome collaborates with regulation of their auto-inhibitory changes fine-tunes the precision of H3K36me in mediating dimethylation by NSD2 and NSD3 as well as trimethylation by Set2/SETD2. The identification of specific structural features and various cis-acting factors that bind to different forms of H3K36me, particularly the di-(H3K36me2) and tri-(H3K36me3) methylated forms of H3K36, have highlighted the intricacy of H3K36me functional significance. Here, we consolidate these findings and offer structural insight to the regulation of H3K36me2 to H3K36me3 conversion. We also discuss the mechanisms that underlie the cooperation between H3K36me and other chromatin modifications (in particular, H3K27me3, H3 acetylation, DNA methylation and N6-methyladenosine in RNAs) in the physiological regulation of the epigenomic functions of chromatin.

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Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate metabolic pathway, and its loss of function through polymorphisms is often associated with human conditions, including cancer, congenital heart disease, and Down syndrome. MTHFR is also required in the maintenance of heterochromatin, a crucial determinant of genomic stability and precise chromosomal segregation. Here, we characterize the function of a fission yeast gene met11+, which encodes a protein that is highly homologous to the mammalian MTHFR. We show that, although met11+ is not essential for viability, its disruption increases chromosome missegregation and destabilizes constitutive heterochromatic regions at pericentromeric, sub-telomeric and ribosomal DNA (rDNA) loci. Transcriptional silencing at these sites were disrupted, which is accompanied by the reduction in enrichment of histone H3 lysine 9 dimethylation (H3K9me2) and binding of the heterochromatin protein 1 (HP1)-like Swi6. The met11 null mutant also dominantly disrupts meiotic fidelity, as displayed by reduced sporulation efficiency and defects in proper partitioning of the genetic material during meiosis. Interestingly, the faithful execution of these meiotic processes is synergistically ensured by cooperation among Met11, Rec8, a meiosis-specific cohesin protein, and the shugoshin protein Sgo1, which protects Rec8 from untimely cleavage. Overall, our results suggest a key role for Met11 in maintaining pericentromeric heterochromatin for precise genetic inheritance during mitosis and meiosis.