H3K36 Methylation Antagonizes PRC2-mediated H3K27 Methylation

Abstract

H3K27 methylation mediated by the histone methyltransferase complex PRC2 is critical for transcriptional regulation, Polycomb silencing, Drosophila segmentation, mammalian X chromosome inactivation, and cancer. PRC2-mediated H3K27 methylation can spread along the chromatin and propagate the repressive chromatin environment; thus, chromatin components that antagonize the activity of PRC2 are important for restraining Polycomb silencing. Here we report that in HeLa cells, H3 histones unmethylated at Lys-36 are mostly methylated at Lys-27, with the exception of newly synthesized H3. In addition, K27me3 rarely co-exists with K36me2 or K36me3 on the same histone H3 polypeptide. Moreover, PRC2 activity is greatly inhibited on nucleosomal substrates with preinstalled H3K36 methylation. These findings collectively identify H3K36 methylation as a chromatin component that restricts the PRC2-mediated spread of H3K27 methylation. Finally, we provide evidence that the controversial histone lysine methyltransferase Ash1, a known Trithorax group protein that antagonizes Polycomb silencing in vivo, is an H3K36-specific dimethylase, not an H3K4 methylase, further supporting the role of H3K36 methylation in antagonizing PRC2-mediated H3K27 methylation.

Physical coupling of activation and derepression activities to maintain an active transcriptional state at FLC

“…S1), so the SDG8-ELF6 interaction is probably independent of transcriptional elongation. The mutually exclusive pattern between H3K27me3 and H3K36me3 has been found in several other systems (2,35,36) and could be explained by the observation that H3K36me3 can inhibit PRC2 activity (37). Our data here provide another possible explanation: that H3K36me3 antagonizes PRC2 repression by codelivering H3K27 demethylase activity with the H3K36 methyltransferase.…”

Antisense COOLAIR mediates the coordinated switching of chromatin states at FLC during vernalization

“…Candidate COOLAIR interacting H3K36 methyltransferase enzymes could be EARLY FLOWERING IN SHORT DAYS (EFS) (24,25), AtPAF1c-mutant VIP4 methyltransferase (26), or Ash1 homologs. Reports have shown that the conserved Trithorax group protein Ash1 is an H3K36-specific dimethylase (27,28). In Arabidopsis, the Ash1 homolog SDG4 was shown to methylate H3K4 and H3K36 (29).…”

Histone H2A Ubiquitination Inhibits the Enzymatic Activity of H3 Lysine 36 Methyltransferases

“…We, and others, have previously reported that H3K36 methylation rarely coexists with H3K27me3 on the same H3 polypeptides (19,38), suggesting that these two modifications may antagonize each other. Indeed, the catalytic activity of PRC2 is inhibited in cis by di-or tri-methylation at lysine 36 of the same H3 histones (19,39,40).…”

“…Indeed, the catalytic activity of PRC2 is inhibited in cis by di-or tri-methylation at lysine 36 of the same H3 histones (19,39,40). However, H3K27me3 does not inhibit * This work was supported by Chinese Ministry of Science and Technology FIGURE 1.…”

“…In budding yeast, Set2 is the sole H3K36-specific methyltransferase (9). In higher eukaryotes, several enzymes have been reported to be H3K36-specific methyltransferases (7), including HYPB, which is the primary H3K36-specific trimethylase (10 -12), and NSD1, NSD2, NSD3, and ASH1L, which are best characterized as H3K36-specific dimethylases (13)(14)(15)(16)(17)(18)(19).…”