The Set1 complex is dimeric and acts with Jhd2 demethylation to convey symmetrical H3K4 trimethylation

Abstract

Epigenetic modifications can maintain or alter the inherent symmetry of the nucleosome. However, the mechanisms that deposit and/or propagate symmetry or asymmetry are not understood. Here we report that yeast Set1C/ COMPASS (complex of proteins associated with Set1) is dimeric and, consequently, symmetrically trimethylates histone 3 Lys4 (H3K4me3) on promoter nucleosomes. Mutation of the dimer interface to make Set1C monomeric abolished H3K4me3 on most promoters. The most active promoters, particularly those involved in the oxidative phase of the yeast metabolic cycle, displayed H3K4me2, which is normally excluded from active promoters, and a subset of these also displayed H3K4me3. In wild-type yeast, deletion of the sole H3K4 demethylase, Jhd2, has no effect. However, in monomeric Set1C yeast, Jhd2 deletion increased H3K4me3 levels on the H3K4me2 promoters. Notably, the association of Set1C with the elongating polymerase was not perturbed by monomerization. These results imply that symmetrical H3K4 methylation is an embedded consequence of Set1C dimerism and that Jhd2 demethylates asymmetric H3K4me3. Consequently, rather than methylation and demethylation acting in opposition as logic would suggest, a dimeric methyltransferase and monomeric demethylase cooperate to eliminate asymmetry and focus symmetrical H3K4me3 onto selected nucleosomes. This presents a new paradigm for the establishment of epigenetic detail.

MLL4 is required after implantation whereas MLL3 becomes essential during late gestation

“…Incomplete penetrance in a developmental choice indicates that MLL4 does not make the choice but rather reduces the error rate by either stabilizing the choice or counteracting mistakes. A primary role for epigenetic regulation in choice stabilization and error reduction concords with our recent findings in yeast where Set1C and the H3K4me3 demethylase Jhd2 act together as a quality control mechanism to ensure symmetrically trimethylated nucleosomes (Choudhury et al, 2019).…”

Histone sumoylation and chromatin dynamics

“…H2B ubiquitylation appears at an early stage among the dynamic changes in histone PTMs and chromatin during transcription; it is preferentially enriched across transcribed regions and correlates positively with transcriptional gene activity ( 64–66 ) (Figure 4B ). In turn, H3K4 methylation, which requires H2BK123 ubiquitylation, is distributed in distinct gradients relative to the transcribed DNA sequence that depend on the extent of H3K4 methylation ( 56 , 67 ). The genome-wide localization pattern of SUMO-modified histones correlates closely with the H3K4me2 profile on actively transcribed genes ( 45 ), supporting the idea that these two modifications contribute to the same or a similar step of chromatin-mediated transcription.…”

Ready, SET, Go: Post-translational regulation of the histone lysine methylation network in budding yeast

“…This macromolecular structure has been shown to be stabilized by an electrostatic interaction between a small basic patch within the N-SET domain of Set1p and an acidic patch toward the C-terminus of Swd1p ( 179 ). Crucially, the COMPASS complex forms a dimeric macromolecule in vivo, via the Sdc1p dimer interface, allowing COMPASS to efficiently deposit methylation at both copies of histone H3 within a single nucleosome ( 188 ). This symmetric H3K4 methylation by Set1p is the only known example of such a phenomenon in budding yeast.…”