Crystal Structure of the COMPASS H3K4 Methyltransferase Catalytic Module

Hsu, Peter L.; Li, Heng; Lau, Ho-Tak; Leonen, Calvin Jon Antolin; Dhall, Abhinav; Ong, Shao‐En; Chatterjee, Champak; Zheng, Ning

doi:10.1016/j.cell.2018.06.038

Cited by 85 publications

(88 citation statements)

References 64 publications

(84 reference statements)

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“…These findings present a new paradigm for the mechanics of H3K4 methylation and demethylation in eukaryotic epigenetic regulation. Furthermore, our findings extend the recent insights acquired from the high-resolution structures of the monomeric Set1C/ COMPASS enzymatic core (Hsu et al 2018;Qu et al 2018).…”

supporting

confidence: 84%

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

Choudhury¹,

Singh²,

Arumugam

et al. 2019

Genes Dev.

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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.

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supporting

confidence: 84%

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

Choudhury¹,

Singh²,

Arumugam

et al. 2019

Genes Dev.

View full text Add to dashboard Cite

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“…7). This proposition has several implications that we first discuss in the light of the recent high resolution structures of the Set1C enzymatic core (Hsu et al 2018;Qu et al 2018).…”

Section: Discussionmentioning

confidence: 94%

“…In both structures, all five components are monomeric except Sdc1, which is a dimer based on the RIIa dimer interface. One Sdc1 interacts with Bre2 though the Bre2 interaction motif and the other Bre2 interaction motif is exposed (Hsu et al 2018).…”

Section: Discussionmentioning

confidence: 99%

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

Choudhury

Singh

Arumugam

et al. 2018

Preprint

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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 is dimeric and consequently symmetrically trimethylates histone 3 lysine 4 (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 monomerisation. 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 co-operate to eliminate asymmetry and focus symmetrical H3K4me3 onto selected nucleosomes.This presents a new paradigm for the establishment of epigenetic detail.

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“…The ubiquitin L70-L73 patch required to stimulate Dot1L is also required to stimulate COMPASS (Holt et al, 2015), although mutations in the basic H4 tail residues that are required for Dot1 activity have no effect on H3K4 methylation (Fingerman et al, 2007). Structures of a 5and 6-protein COMPASS subcomplex were recently reported (Hsu et al, 2018;Qu et al, 2018), but it is not known how this complex recognizes ubiquitin or the nucleosome.…”

Section: Discussionmentioning

confidence: 99%

The mechanism of cross-talk between histone H2B ubiquitination and H3 methylation by Dot1L

Worden

Hoffmann

Hicks

et al. 2018

Preprint

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Methylation of histone H3, lysine 79 (H3K79), by Dot1L is a hallmark of actively transcribed genes that depends on monoubiquitination of H2B at lysine 120 (H2B-Ub), and is a well-characterized example of histone modification cross-talk that is conserved from yeast to humans. The mechanism by which H2B-Ub stimulates Dot1L to methylate the relatively inaccessible histone core H3K79 residue is unknown. The 3.0 Å resolution cryo-EM structure of Dot1L bound to ubiquitinated nucleosome reveals that Dot1L contains binding sites for both ubiquitin and the histone H4 tail, which establish two regions of contact that stabilize a catalytically competent state and positions the Dot1L active site over H3K79. We unexpectedly find that contacts mediated by both Dot1L and the H4 tail induce a conformational change in the globular core of histone H3 that reorients K79 from an inaccessible position, thus enabling this side chain to project deep into the active site in a position primed for catalysis. Our study provides a comprehensive mechanism of cross-talk between histone ubiquitination and methylation and reveals an unexpected structural plasticity in histones that makes it possible for histone-modifying enzymes to access residues within the nucleosome core.

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Crystal Structure of the COMPASS H3K4 Methyltransferase Catalytic Module

Cited by 85 publications

References 64 publications

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

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

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

The mechanism of cross-talk between histone H2B ubiquitination and H3 methylation by Dot1L

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