Structural and functional specificity of H3K36 methylation

Abstract

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.

Histone methyltransferase SETD2: An epigenetic driver in clear cell renal cell carcinoma

“…The AWS-SET-PS domains are essential as a catalytic methyltransferase domain for H3K36me3; the AWS and post-SET domains are flanked onto the SET domain at the N- and C-terminally, respectively. All methylation of H3K36me2 to H3K36me3 depends on the SET domain, with S-adenosylmethionine (SAM) as the cofactor, providing an additional methyl ( 10 ). It is reported that the H3K36M oncohistone mutation inhibits SETD2 methyltransferase activity; the structure of the SETD2-H3K36M-SAM complex suggests that SAM indirectly affects the SETD2-H3K36M interaction and maintains the SET domain in the proper fold state ( 11 ).…”

Transcriptional regulation of macrophages in heart failure

“…Histone methylation is related to transcriptional inhibition as well as transcriptional activation. For example, H3K4me2/3 ( 37 ), H3K36me1/3 ( 38 ), and H3K79me1/2 ( 39 ) are associated with transcriptional activation, and H3K27me2/3 ( 40 ) and H3K9me2/3 ( 41 ) are associated with transcriptional inhibition ( 42 ). Histone acetylation is regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) mediates the process of deacetylation.…”

Nucleosomes and flipons exchange energy to alter chromatin conformation, the readout of genomic information, and cell fate

“…Another question is whether formation of Z‐DNA also exposes the H3 tails to modification by methylation at either H3K27 or H3K36 as both histone marks require local transcription, with the former mark enhancing gene expression while the later can result in suppression. [ 61 ]…”