In mammalian cells, SETD2 is recruited to the RNAPII elongation complex through an Spt6:Iws axis. Through this process, cells maintain the deacetylated chromatin to inhibit the cryptic transcription. In yeast, Set2 secures H3K36me3 co-transcriptionally and recruits the reduced potassium dependency 3 small (Rpd3S) through its chromodomain-containing subunit ESA1 associated factor 3 (Eaf3), which will then subsequently deacetylate histones around the transcribed gene body regions. In addition, H3K36me3 acts as a safeguard to prevent aberrant transcriptional initiation from cryptic gene promoters. Genome-wide studies show that H3K36me3 distributes in the gene body in a 3′ end enriched manner like the Ser2 phosphorylated RNAPII. SETD2, the methyltransferase for H3K36me3, is recruited through the Ser2 phosphorylated C-terminal domain (CTD) of RNA polymerase II (RNAPII) during gene transcription elongation, while the Ser5 phosphorylation of RNAPII is the characteristic of the paused polymerases at promoters. H3K36me3 is tightly correlated with actively transcribed genome regions. Several lines of evidences have shown that H3K36me3 plays a role in the transcriptional activation. SETD2, the paralogous protein of Set2, is the only enzyme found to catalyze the formation of H3K36me3, while there are still arguments that it also methylates H3K36 to H3K36me1 and H3K36me2 in vivo. In mammalian cells, several redundant enzymes, including NSD1, NSD2, NSD3, ASH1L, SETD3, SETMAR, and SMYD2, are able to mono- and di-methylate H3K36. In yeast, Set2 is the solo enzyme responsible for all of these three forms of methylations. Histone H3 is methylated at lysine 36 (H3K36) with mono-, di- and tri-methylations (H3K36me1/me2/me3). Histone methylations usually occur on the arginine or lysine residues. Different modifications have been reported, at least by Mass Spectrometry analysis, on core histones, of which the mostly studied modifications are methylation, acetylation, phosphorylation, ubiquitylation and SUMOylation. The N- and C-terminal tails of core histones are enriched with basic amino acids and may undergo post-translational modifications during distinct cellular processes, such as gene transcription, cell cycle checkpoint, centromere assembly, heterochromatin formation, DNA replication and DNA repair. Nucleosome, the smallest subunit of chromatin, consists of 146–147 base pairs of DNAs wrapped around an octamer of core histone proteins, including one H2A–H2B tetramer and two H3–H4 dimers. In eukaryotes, the genomic DNA is packaged into chromatin to maintain the higher order structure.
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