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SUMOylation enhances DNMT1 function to repress mega-intergenic RNAs and viral mimicry [Nanopore]

ABSTRACT: DNA methyltransferase 1 (DNMT1) is essential for mammalian development and is frequently dysregulated in cancer. While its recruitment to hemi-methylated DNA by UHRF1 is well established, its broader chromatin occupancy and regulation remain unclear. We show that DNMT1 is enriched at unmethylated CpG islands of actively transcribed genes largely by its CXXC domain. Upon selective catalytic inhibition, DNMT1 redistributes to partially methylated, inaccessible regions in a UHRF1- and RFTS-dependent manner. Despite minimal changes in coding gene expression, sustained DNMT1 inhibition and subsequent global DNA hypomethylation trigger reactivation of a previously uncharacterised class of dsRNA mega-intergenic transcripts (mintRNAs) driving a cell-intrinsic viral mimicry response. We identify RNF4 as a major regulator of DNMT1 catalytic function that, beyond its canonical role in DNA–protein crosslink resolution, controls the levels of SUMOylated DNMT1, establishing SUMOylation as a rheostat that regulates DNMT1 activity to maintain DNA methylation and safeguard against viral mimicry.

ORGANISM(S): Homo sapiens

PROVIDER: GSE329596 | GEO | 2026/05/17

REPOSITORIES: GEO

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SUMOylation enhances DNMT1 function to repress mega-intergenic RNAs and viral mimicry

Project description:DNA methyltransferase 1 (DNMT1) is essential for mammalian development and is frequently dysregulated in cancer. While its recruitment to hemi-methylated DNA by UHRF1 is well established, its broader chromatin occupancy and regulation remain unclear. We show that DNMT1 is enriched at unmethylated CpG islands of actively transcribed genes largely by its CXXC domain. Upon selective catalytic inhibition, DNMT1 redistributes to partially methylated, inaccessible regions in a UHRF1- and RFTS-dependent manner. Despite minimal changes in coding gene expression, sustained DNMT1 inhibition and subsequent global DNA hypomethylation trigger reactivation of a previously uncharacterised class of dsRNA mega-intergenic transcripts (mintRNAs) driving a cell-intrinsic viral mimicry response. We identify RNF4 as a major regulator of DNMT1 catalytic function that, beyond its canonical role in DNA–protein crosslink resolution, controls the levels of SUMOylated DNMT1, establishing SUMOylation as a rheostat that regulates DNMT1 activity to maintain DNA methylation and safeguard against viral mimicry.

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Project description:Site-specific hypermethylation of tumor suppressor genes accompanied by genome-wide hypomethylation are epigenetic hallmarks of malignancy. However, molecular mechanisms that drive these linked changes in DNA methylation remain obscure. DNA methyltransferase 1 (DNMT1), the principle enzyme responsible for maintaining methylation patterns is commonly dysregulated in tumors. Replication foci targeting sequence (RFTS) is an N-terminal domain of DNMT1 that inhibits DNA-binding and catalytic activity, suggesting that RFTS deletion would result in gain of DNMT1 function. However, earlier data suggested that RFTS is required for DNMT1 activity. Here, we determined cellular consequences of RFTS deletion from DNMT1 in immortalized human bronchial epithelial cells. Compared to full-length DNMT1, ectopic expression of DNMT1- ?RFTS caused greater malignant transformation and enhanced promoter methylation that silenced DAPK and DUOX1 gene expression and increased intensity of promoter methylation across the genome. Strikingly, DNMT1-?RFTS also produced genomic hypomethylation and demethylation of Satellite 2 repeat sequences. Because deletion of RFTS is sufficient to induce focal hypermethylation and global hypomethylation in parallel, evidence suggests that the RFTS domain is a target responsible for epigenetic changes in cancer. DNA samples from HBEC3 cells transfected with vector control and HBEC3 cells with full-length and RFTS-deleted DNMT1 were assessed for genome-wide methylation using the microarray-based high resolution HpaII tiny fragment enriched by ligation-mediated PCR (HELP) assay.

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Project description:Site-specific hypermethylation of tumor suppressor genes accompanied by genome-wide hypomethylation are epigenetic hallmarks of malignancy. However, molecular mechanisms that drive these linked changes in DNA methylation remain obscure. DNA methyltransferase 1 (DNMT1), the principle enzyme responsible for maintaining methylation patterns is commonly dysregulated in tumors. Replication foci targeting sequence (RFTS) is an N-terminal domain of DNMT1 that inhibits DNA-binding and catalytic activity, suggesting that RFTS deletion would result in gain of DNMT1 function. However, earlier data suggested that RFTS is required for DNMT1 activity. Here, we determined cellular consequences of RFTS deletion from DNMT1 in immortalized human bronchial epithelial cells. Compared to full-length DNMT1, ectopic expression of DNMT1- ΔRFTS caused greater malignant transformation and enhanced promoter methylation that silenced DAPK and DUOX1 gene expression and increased intensity of promoter methylation across the genome. Strikingly, DNMT1-ΔRFTS also produced genomic hypomethylation and demethylation of Satellite 2 repeat sequences. Because deletion of RFTS is sufficient to induce focal hypermethylation and global hypomethylation in parallel, evidence suggests that the RFTS domain is a target responsible for epigenetic changes in cancer.

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Project description:DNA methylation is a heritable chromatin modification essential to mammalian development that functions with histone post-translational modifications to regulate chromatin structure and gene expression programs. The epigenetic inheritance of DNA methylation requires the combined actions of DNMT1 and UHRF1, a histone- and DNA-binding RING E3 ubiquitin ligase that facilitates DNMT1 recruitment to sites of newly replicated DNA through the ubiquitylation of histone H3. UHRF1 binds DNA with modest selectivity towards hemi-methylated CpG dinucleotides (HeDNA); however, the contribution of HeDNA sensing to UHRF1 function remains elusive. Here, we reveal that the interaction of UHRF1 with HeDNA is required for DNA methylation inheritance but is dispensable for chromatin interaction, which is governed by reciprocal positive cooperativity between the UHRF1 histone- and DNA-binding domains. We further show that HeDNA functions as an allosteric regulator of UHRF1 ubiquitin ligase activity, directing ubiquitylation towards multiple lysines on the H3 tail adjacent to the UHRF1 histone-binding site. Collectively, our studies define a highly orchestrated epigenetic control mechanism involving modifications both to histones and DNA that facilitate UHRF1 chromatin targeting, H3 ubiquitylation, and DNA methylation inheritance.

2016-08-25 | PXD003983 | Pride

Histone ubiquitination-methylation crosstalk involving UHRF1 and SUV39H1/2 reinforces heterochromatin states in response to DNA hypomethylation

Project description:Histone H3 mono-ubiquitination, catalyzed by the RING E3 ubiquitin ligase UHRF1, is appreciated as a docking site for DNMT1 during DNA replication to facilitate DNA methylation maintenance. Its functions beyond this are unknown. Here, we identify simultaneous increases in UHRF1-dependent H3K18ub and SUV39H1/2-dependent H3K9me3 as prominent epigenetic alterations accompanying DNA hypomethylation induced by DNMT1 inhibition. Integrative epigenomics analyses reveal that transient accumulation of hemi-methylated DNA, resulting from incomplete DNA methylation maintenance, stimulates UHRF1-dependent H3K18ub at CpG islands that nucleates new domains of H3K9me3 and impedes PRC2 activity in these genomic regions. Notably, H3K18ub enhances the methyltransferase activity of SUV39H1/2, leading to increased H3K9me3 at these CpG island promoters. Blocking H3K18ub-dependent SUV39H1/2 activity enhances the efficacy of DNMT1 inhibitors. Collectively, these findings reveal a novel histone ubiquitination-methylation crosstalk mechanism that reinforces heterochromatin states in the absence of DNA methylation and proposes new strategies for improving cancer epigenetic therapy.

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Project description:The multi-domain protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 for DNA methylation maintenance during DNA replication. Here, we show that MOF (Males absent On the First) is an acetyltransferase of UHRF1 to acetylate UHRF1 at Lys670 in the pre-RING linker region whereas HDAC1 is a deacetylase of UHRF1 at the same site. The MOF/HDAC1-mediated acetylation in UHRF1 is cell-cycle regulated and peaks at G1/S phase, in line with the function of UHRF1 in recruiting DNMT1 to maintain DNA methylation. In addition, UHRF1 acetylation significantly enhances its E3 ligase activity and elimination of UHRF1 acetylation at these sites attenuates UHRF1-mediated H3 ubiquitination, which in turn impairs the DNMT1 recruitment and DNA methylation. Taken together, these findings not only identify MOF as a new acetyltransferase for UHRF1 but also reveal a novel mechanism underlying the regulation of DNA methylation maintenance through MOF-mediated UHRF1 acetylation.

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