Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation

Ren, Wendan; Fan, Huitao; Grimm, Sara A.; Guo, Yiran; Kim, Jae Jin; Li, Linhui; Petell, Christopher J.; Tan, Xiao-Feng; Zhang, Zhimin; Coan, John P.; Yin, Jiekai; Gao, Linfeng; Cai, Ling; Detrick, Brittany; Çetin, Burak; Patel, Dinshaw J.; Wang, Yinsheng; Cui, Qiang; Strahl, Brian D.; Gozani, Or; Miller, Kyle M.; O’Leary, Seán E.; Wade, Paul A.; Wang, Gang Greg; Song, Jikui

doi:10.1101/2020.04.27.064493

Cited by 9 publications

(11 citation statements)

References 71 publications

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“…1 and see method). As expected from previous work 12,13 , the addition of H3Ub2 enhanced the enzymatic activity of DNMT1 (Extended Data Fig. 1d,e).…”

Section: Resultssupporting

confidence: 91%

“…An E3 ubiquitin ligase (ubiquitin-like containing PHD and RING finger domains 1, UHRF1) protein, plays a crucial role for maintenance DNA methylation 5,6 , together with DNMT1. UHRF1 recognizes hemimethylated DNA via its SET and RING-associated (SRA) [7][8][9] and catalyzes double monoubiquitination at K18 and K23 on histone H3 (H3Ub2) which, in turn, recruits DNMT1 and stimulates its enzymatic activity [10][11][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for activation of DNMT1

Onoda

Kikuchi

Yamaguchi

et al. 2022

Preprint

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DNMT1 is an essential enzyme that maintains genomic DNA methylation, and its function is regulated by mechanisms that are not yet fully understood. Here, we report the cryo-EM structure of nearly full-length human DNMT1 bound to its two natural activators: hemimethylated DNA and ubiquitinated histone H3. We find that a hitherto unstudied linker, between the RFTS and CXXC domains, plays a key role for activation. It contains a conserved α-helix which engages a crucial "Toggle" pocket, displacing a previously described inhibitory linker, and allowing the DNA recognition helix to spring into the active conformation. This is accompanied by large-scale reorganization of the inhibitory RFTS and CXXC domains, allowing the enzyme to gain full activity. Our results therefore provide a mechanistic basis for the activation of DNMT1, with consequences for basic research and drug design.

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“…1 and see method). As expected from previous work 12,13 , the addition of H3Ub2 enhanced the enzymatic activity of DNMT1 (Extended Data Fig. 1d,e).…”

Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Structural basis for activation of DNMT1

Onoda

Kikuchi

Yamaguchi

et al. 2022

Preprint

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“…We speculate the more interesting possibility: endogenous BPTF is subject to regulation that further refines its chromatin localization beyond simple availability of H3K4me3 / H3K18ac for its C-terminal PHD-BD. Indeed, there are increasing examples of auto-regulatory elements within CAPs that modulate their activity [64][65][66][67][68][69][70][71][72][73][74][75][76][77][78] , suggesting that a histone code is more than the simple availability of potentially redundant positive signals.…”

Section: Discussionmentioning

confidence: 99%

Nucleosome conformation dictates the histone code

Marunde

Fuchs

Burg

et al. 2022

Preprint

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Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized "codes" that are read by specialized regions (reader domains) in chromatin associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP-histone PTM] specificity, and thus decipher the histone code / guide epigenetic therapies. However, this has largely been done using a reductive approach of isolated reader domains and histone peptides, with the assumption that PTM readout is unaffected by any higher order factors. Here we show that CAP-histone PTM interaction is in fact dependent on nucleosome context. Our results indicate this is due to histone tail accessibility and the associated impact on binding potential of reader domains. We further demonstrate that the in vitro specificity of a tandem reader for PTM-defined nucleosomes is recapitulated in a cellular context. This necessitates we refine the "histone code" concept and interrogate it at the nucleosome level.

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“…Finally, in addition to recognizing H3K18 and H3K23 ubiquitination catalyzed by UHRF1, a recent study demonstrates that the RFTS domain of DNMT1 also specifically binds to H3K9me3 (Ren et al , 2020). It was proposed that the direct interaction between DNMT1‐RFTS and H3K9me3 in conjunction with H3 mono‐ubiquitination could compensate for the loss of UHRF1‐TTD to maintain CpG methylation.…”

Section: Introductionmentioning

confidence: 99%

The interplay between DNA and histone methylation: molecular mechanisms and disease implications

Chen

Lü

2021

EMBO Reports

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Methylation of cytosine in CpG dinucleotides and histone lysine and arginine residues is a chromatin modification that critically contributes to the regulation of genome integrity, replication, and accessibility. A strong correlation exists between the genome-wide distribution of DNA and histone methylation, suggesting an intimate relationship between these epigenetic marks. Indeed, accumulating literature reveals complex mechanisms underlying the molecular crosstalk between DNA and histone methylation. These in vitro and in vivo discoveries are further supported by the finding that genes encoding DNA-and histone-modifying enzymes are often mutated in overlapping human diseases. Here, we summarize recent advances in understanding how DNA and histone methylation cooperate to maintain the cellular epigenomic landscape. We will also discuss the potential implication of these insights for understanding the etiology of, and developing biomarkers and therapies for, human congenital disorders and cancers that are driven by chromatin abnormalities.

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Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation

Cited by 9 publications

References 71 publications

Structural basis for activation of DNMT1

Structural basis for activation of DNMT1

Nucleosome conformation dictates the histone code

The interplay between DNA and histone methylation: molecular mechanisms and disease implications

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