Two competing mechanisms of DNMT3A recruitment regulate the dynamics of de novo DNA methylation at PRC1-targeted CpG islands

Weinberg, Daniel N.; Rosenbaum, Phillip; Chen, Xiao; Barrows, Douglas; Horth, Cynthia; Marunde, Matthew R.; Popova, Irina K; Gillespie, Zachary B; Keogh, Michael Christopher; Lü, Chao; Majewski, Jacek; Allis, C. David

doi:10.1038/s41588-021-00856-5

Cited by 62 publications

(60 citation statements)

References 45 publications

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“…Together, these observations primarily favor a titration model that is further supported by reduced PRC2 occupancy at target sites. Alternatively, a number of new H2AK119ub1 sensors have been reported recently ( McBride et al., 2020 ; Weinberg et al., 2021 ), but their effective role in PR-DUB- and PRC1-related processes remains to be fully established.…”

Section: Discussionmentioning

confidence: 99%

BAP1 enhances Polycomb repression by counteracting widespread H2AK119ub1 deposition and chromatin condensation

et al. 2021

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Summary BAP1 is mutated or deleted in many cancer types, including mesothelioma, uveal melanoma, and cholangiocarcinoma. It is the catalytic subunit of the PR-DUB complex, which removes PRC1-mediated H2AK119ub1, essential for maintaining transcriptional repression. However, the precise relationship between BAP1 and Polycombs remains elusive. Using embryonic stem cells, we show that BAP1 restricts H2AK119ub1 deposition to Polycomb target sites. This increases the stability of Polycomb with their targets and prevents diffuse accumulation of H2AK119ub1 and H3K27me3. Loss of BAP1 results in a broad increase in H2AK119ub1 levels that is primarily dependent on PCGF3/5-PRC1 complexes. This titrates PRC2 away from its targets and stimulates H3K27me3 accumulation across the genome, leading to a general chromatin compaction. This provides evidence for a unifying model that resolves the apparent contradiction between BAP1 catalytic activity and its role in vivo , uncovering molecular vulnerabilities that could be useful for BAP1-related pathologies.

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Section: Discussionmentioning

confidence: 99%

BAP1 enhances Polycomb repression by counteracting widespread H2AK119ub1 deposition and chromatin condensation

et al. 2021

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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

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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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“…Indeed, we find that the subset of DMS germline genes bound by MGA/MAX and E2F6 actually show delayed DNAme both in vitro and in vivo relative to the DMS germline genes not enriched for PRC1.6. While H2AK119ub1 79 and/or SETDB1 80 may play a direct role in recruitment of the de novo DNMTs, inhibition/removal of H3K4 trimethylation is likely a universal prerequisite for de novo DNAme of DMS germline gene promoters 81 – 83 . As H3K36 di- and tri-methylation also promote de novo DNAme in intergenic and intragenic regions, respectively 84 – 86 , methylation of this H3 residue may also play a role at germline genes.…”

Section: Discussionmentioning

confidence: 99%

Repression of germline genes by PRC1.6 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing

et al. 2021

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Silencing of a subset of germline genes is dependent upon DNA methylation (DNAme) post-implantation. However, these genes are generally hypomethylated in the blastocyst, implicating alternative repressive pathways before implantation. Indeed, in embryonic stem cells (ESCs), an overlapping set of genes, including germline “genome-defence” (GGD) genes, are upregulated following deletion of the H3K9 methyltransferase SETDB1 or subunits of the non-canonical PRC1 complex PRC1.6. Here, we show that in pre-implantation embryos and naïve ESCs (nESCs), hypomethylated promoters of germline genes bound by the PRC1.6 DNA-binding subunits MGA/MAX/E2F6 are enriched for RING1B-dependent H2AK119ub1 and H3K9me3. Accordingly, repression of these genes in nESCs shows a greater dependence on PRC1.6 than DNAme. In contrast, GGD genes are hypermethylated in epiblast-like cells (EpiLCs) and their silencing is dependent upon SETDB1, PRC1.6/RING1B and DNAme, with H3K9me3 and DNAme establishment dependent upon MGA binding. Thus, GGD genes are initially repressed by PRC1.6, with DNAme subsequently engaged in post-implantation embryos.

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Two competing mechanisms of DNMT3A recruitment regulate the dynamics of de novo DNA methylation at PRC1-targeted CpG islands

Cited by 62 publications

References 45 publications

BAP1 enhances Polycomb repression by counteracting widespread H2AK119ub1 deposition and chromatin condensation

BAP1 enhances Polycomb repression by counteracting widespread H2AK119ub1 deposition and chromatin condensation

Nucleosome conformation dictates the histone code

Repression of germline genes by PRC1.6 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing

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