Dominant negative effects on H3K27 methylation by Weaver syndrome-associated EZH2 variants

Deevy, Orla; Monger, Craig; Matrà, Francesca; Tuck, Ellen; Conway, Eric; Badonyi, Mihaly; Nimmo, Darragh; Rodighiero, Simona; Zhang, Qi; Davidovich, Chen; Marsh, Joseph A.; Pasini, Diego; Bracken, Adrian P.

doi:10.1101/2023.06.01.543208

Cited by 3 publications

(1 citation statement)

References 101 publications

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“…In mammals, the fundamental importance of 5mC and H3K27me3 is highlighted by embryonic lethality in mouse knockout studies 7–11 as well as grossly perturbed 5mC and/or H3K27me3 landscapes in a number of cancers 12–14 . Curiously, mutations in both 5mC and PRC2 machinery are also associated with human overgrowth syndromes 15–19 . The shared ontogenic manifestations of 5mC- and H3K27me3-linked syndromes raise questions about the interplay between the two forms of transcriptional control.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation shapes the Polycomb landscape during the exit from naïve pluripotency

Albert,

Urli,

Monteagudo-Sánchez

et al. 2023

Preprint

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In mammals, 5 methyl-cytosine (5mC) and Polycomb Repressive Complex 2 (PRC2)- deposited histone 3 lysine 27 trimethylation (H3K27me3) are generally mutually exclusive at CpG-rich regions. As mouse embryonic stem cells exit the naïve pluripotent state, there is a massive gain of 5mC coincident with a restriction of broad H3K27me3 to 5mC-free, CpG-rich regions. To formally assess how 5mC shapes the H3K27me3 landscape, we profiled the epigenome of naïve and differentiated cells in the presence and absence of the DNA methylation machinery. Surprisingly, we found that 5mC accumulation is not required to restrict most H3K27me3 domains. We went on to show that this 5mC-independent H3K27me3 restriction is mediated by aberrant expression of the PRC2 antagonistEzhip. At the regions where 5mC appears to genuinely supplant H3K27me3, we identified 68 candidate genes that appeared to require 5mC deposition and/or H3K27me3 depletion for their activation in differentiated cells. Employing site-directed epigenome editing to directly modulate 5mC levels, we demonstrated that 5mC deposition is sufficient to antagonize H3K27me3 deposition and confer gene activation at individual candidates. Altogether, we systematically measured the antagonistic interplay between 5mC and H3K27me3 in a system that recapitulates early embryonic dynamics. Our results suggest that H3K27me3 restraint depends on 5mC, both directly and indirectly. This study also reveals a non-canonical role of 5mC in gene activation, which may be important not only for normal development but also for cancer progression, as oncogenic cells frequently exhibit dynamic replacement of 5mC for H3K27me3 and vice versa.

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Section: Introductionmentioning

confidence: 99%

DNA methylation shapes the Polycomb landscape during the exit from naïve pluripotency

Albert,

Urli,

Monteagudo-Sánchez

et al. 2023

Preprint

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Novel mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition

Gao

Lin

Riddle

et al. 2023

Preprint

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Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in EZH2, which encodes the predominant H3K27 methyltransferase and key enzymatic component of Polycomb repressive complex 2 (PRC2). Weaver syndrome is characterized by striking overgrowth and advanced bone age, intellectual disability, and distinctive facies. We generated a mouse model for the most common Weaver syndrome missense variant, EZH2 p.R684C. Ezh2 R684C/R684C mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3. Ezh2 R684C/+ mice had abnormal bone parameters indicative of skeletal overgrowth, and Ezh2 R684C/+ osteoblasts showed increased osteogenic activity. RNA-seq comparing osteoblasts differentiated from Ezh2 R684C/+ and Ezh2+/+ bone marrow mesenchymal stem cells (BM-MSCs) indicated collective dysregulation of the BMP pathway and osteoblast differentiation. Inhibition of the opposing H3K27 demethylases Kdm6a/6b substantially reversed the excessive osteogenesis in Ezh2 R684C/+ cells both at the transcriptional and phenotypic levels. This supports both the ideas that writers and erasers of histone marks exist in a fine balance to maintain epigenome state, and that epigenetic modulating agents have therapeutic potential for the treatment of MDEMs.

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A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition

Gao,

Lin,

Riddle

et al. 2024

JCI Insight

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Dominant negative effects on H3K27 methylation by Weaver syndrome-associated EZH2 variants

Cited by 3 publications

References 101 publications

DNA methylation shapes the Polycomb landscape during the exit from naïve pluripotency

DNA methylation shapes the Polycomb landscape during the exit from naïve pluripotency

Novel mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition

A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition

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