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

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

doi:10.1073/pnas.2009316117

Cited by 72 publications

(83 citation statements)

References 62 publications

(74 reference statements)

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“…The BAH1–H4K20me3 binding-mediated allosteric activation of DNMT1 is reminiscent of the previously reported RFTS–H3K9me3Ub2 readout 29 . We therefore asked how the BAH1–H4K20me3 and RFTS–H3K9me3Ub2 interactions crosstalk.…”

Section: Resultssupporting

confidence: 68%

“…For instance, the DNMT1 RFTS domain (DNMT1 RFTS ) recognizes ubiquitinated histone H3 (H3Ub) 22 – 25 and PCNA-associated factor 15 (PAF15) 26 , 27 during S phase, which leads to cell cycle-specific chromatin targeting and enzymatic stimulation of DNMT1 23 , 26 , 28 . Our recent study further demonstrated that DNMT1 RFTS also directly recognizes H3K9me3, thereby reinforcing the DNMT1 RFTS -H3Ub readout for the DNA methylation maintenance at heterochromatic regions 29 . Likewise, the DNMT1 CXXC domain specifically recognizes unmodified CpG DNA to control DNMT1-mediated de novo DNA methylation 15 , 30 .…”

Section: Introductionsupporting

confidence: 58%

“…We identified the first BAH domain of DNMT1 (DNMT1 BAH1 ) as a reader for H4K20me3. Strikingly, the H4K20me3 binding by DNMT1 BAH1 causes displacement of the autoinhibitory linker, which frees DNMT1 from the linker-mediated autoinhibition and leads to allosteric stimulation of DNMT1, reminiscent of what was previously observed for the DNMT1 RFTS –H3K9me3Ub interaction 23 , 29 . Consistently, single-molecule Förster resonance energy transfer (smFRET) analysis revealed that the DNMT1 RFTS –H3K9me3Ub and DNMT1 BAH1 –H4K20me3 interactions both trigger fast conformational dynamics of DNMT1, promoting the transition of DNMT1 into an open conformation.…”

Section: Introductionsupporting

confidence: 57%

“…Given that Dnmt1 deletion is lethal to dividing somatic cells, but not mouse ES cells 39 , we turned to mouse ES cells to examine the role of DNMT1 BAH1 in regulating DNA methylation maintenance. Using our recently reported gene complementation system 29 , we introduced comparable levels of exogenous DNMT1 WT or a BAH1-defective mutant (DNMT1 W796A ) into Dnmt1-knockout mouse embryonic stem cells (1KO-ESCs) (Fig. 4a ).…”

Section: Resultsmentioning

confidence: 99%

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DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

et al. 2021

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DNA methylation and trimethylated histone H4 Lysine 20 (H4K20me3) constitute two important heterochromatin-enriched marks that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two chromatin modifications crosstalk. Here, we report that DNA methyltransferase 1 (DNMT1) specifically ‘recognizes’ H4K20me3 via its first bromo-adjacent-homology domain (DNMT1BAH1). Engagement of DNMT1BAH1-H4K20me3 ensures heterochromatin targeting of DNMT1 and DNA methylation at LINE-1 retrotransposons, and cooperates with the previously reported readout of histone H3 tail modifications (i.e., H3K9me3 and H3 ubiquitylation) by the RFTS domain to allosterically regulate DNMT1’s activity. Interplay between RFTS and BAH1 domains of DNMT1 profoundly impacts DNA methylation at both global and focal levels and genomic resistance to radiation-induced damage. Together, our study establishes a direct link between H4K20me3 and DNA methylation, providing a mechanism in which multivalent recognition of repressive histone modifications by DNMT1 ensures appropriate DNA methylation patterning and genomic stability.

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Section: Resultssupporting

confidence: 68%

Section: Introductionsupporting

confidence: 58%

Section: Introductionsupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

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DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

et al. 2021

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“…This intriguing new finding may help to explain our findings as well as those of the aforementioned studies. Our studies and these above-referenced findings also call into question a recent report implicating H3K9me3 recognition directly by DNMT1 as a mechanism that contributes to its DNA methylation maintenance function [50].…”

Section: Discussionsupporting

confidence: 52%

The histone and non-histone methyllysine reader activities of the UHRF1 tandem Tudor domain are dispensable for the propagation of aberrant DNA methylation patterning in cancer cells

Vaughan

Kupai

Foley

et al. 2020

Epigenetics & Chromatin

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The chromatin-binding E3 ubiquitin ligase ubiquitin-like with PHD and RING finger domains 1 (UHRF1) contributes to the maintenance of aberrant DNA methylation patterning in cancer cells through multivalent histone and DNA recognition. The tandem Tudor domain (TTD) of UHRF1 is well-characterized as a reader of lysine 9 di- and tri-methylation on histone H3 (H3K9me2/me3) and, more recently, lysine 126 di- and tri-methylation on DNA ligase 1 (LIG1K126me2/me3). However, the functional significance and selectivity of these interactions remain unclear. In this study, we used protein domain microarrays to search for additional readers of LIG1K126me2, the preferred methyl state bound by the UHRF1 TTD. We show that the UHRF1 TTD binds LIG1K126me2 with high affinity and selectivity compared to other known methyllysine readers. Notably, and unlike H3K9me2/me3, the UHRF1 plant homeodomain (PHD) and its N-terminal linker (L2) do not contribute to multivalent LIG1K126me2 recognition along with the TTD. To test the functional significance of this interaction, we designed a LIG1K126me2 cell-penetrating peptide (CPP). Consistent with LIG1 knockdown, uptake of the CPP had no significant effect on the propagation of DNA methylation patterning across the genomes of bulk populations from high-resolution analysis of several cancer cell lines. Further, we did not detect significant changes in DNA methylation patterning from bulk cell populations after chemical or genetic disruption of lysine methyltransferase activity associated with LIG1K126me2 and H3K9me2. Collectively, these studies identify UHRF1 as a selective reader of LIG1K126me2 in vitro and further implicate the histone and non-histone methyllysine reader activity of the UHRF1 TTD as a dispensable domain function for cancer cell DNA methylation maintenance.

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Targeting polycomb repressor complex 2‐mediated bivalent promoter epigenetic silencing of secreted frizzled‐related protein 1 inhibits cholangiocarcinoma progression

Wu,

Wang,

Wang

et al. 2023

Clinical & Translational Med

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BackgroundCholangiocarcinoma (CCA) refers to a collection of malignancies that are associated with a dismal prognosis. Currently, surgical resection is the only way to cure patients with CCA. Available systemic therapy is limited to gemcitabine plus cisplatin; however, this treatment is palliative in nature. Therefore, there is still a need to explore new effective therapeutic targets to intervene against CCA.MethodsWe analyzed the expression of EZH2 and the prognosis of patients in CCA. The proliferation, migration and invasion of CCA cells after gene knockdown and overexpression were examined and validated by a xenograft model and a primary CCA mouse model with corresponding gene intervention. Targeting DNA methylation, and RNA‐sequencing‐based transcriptomic analysis in EZH2 and SUZ12 knockout CCA cells was performed. Bisulfite sequencing polymerase chain reaction (PCR), chromatin immunoprecipitation‐quantitative PCR (ChIP‐qPCR) and reverse‐ChIP assays were performed for research purposes.ResultsIncreased expression of EZH2 in CCA exhibited a significantly poorer prognosis. DNA hypomethylation of the promoter and increased mRNA levels of secreted frizzled‐related protein 1 (SFRP1) were observed in CCA cells following the inhibition of polycomb repressor complex 2 (PRC2), which was achieved through a knockout of EZH2, SUZ12 and EED, respectively, or treatment with GSK126 and GSK343. Targeting the SFRP1 promoter DNA hypermethylation with dCas9‐DNMT3a decreased the mRNA level of SFRP1. The expression of SFRP1 is regulated by both H3K27me3 and DNA methylation and H3K27me3 plays a crucial role in promoting SFRP1 promotor DNA methylation. GSK343 is a small molecule inhibitor that targets the catalytic activity of EZH2. It effectively inhibits the progression and development of subcutaneous xenografts and primary CCA mouse models.ConclusionOverall, our data strongly suggested that targeting PRC2 promotes the expression of SFRP1, thereby inhibiting the progression of CCA.Key Points/Headlights Cholangiocarcinoma (CCA) exhibits elevated expression of EZH2, SUZ12 and EED, resulting in increased levels of H3K27me3. Targeting polycomb repressor complex 2 (PRC2) leads to the removal of H3K27me3 from the secreted frizzled‐related protein 1 (SFRP1) promoter and DNA hypomethylation, thereby activating the transcription of SFRP1. Inhibiting PRC2, including the use of EZH2 inhibitors, holds promise as a potential strategy for developing anti‐cancer drugs for CCA.

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

Cited by 72 publications

References 62 publications

DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

The histone and non-histone methyllysine reader activities of the UHRF1 tandem Tudor domain are dispensable for the propagation of aberrant DNA methylation patterning in cancer cells

Targeting polycomb repressor complex 2‐mediated bivalent promoter epigenetic silencing of secreted frizzled‐related protein 1 inhibits cholangiocarcinoma progression

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