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Defining UHRF1 Domains That Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties [methylation]

ABSTRACT: Defining UHRF1 Domains That Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties [methylation]

PROVIDER: PRJNA487595 | ENA |

REPOSITORIES: ENA

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Defining UHRF1 Domains That Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties [methylation]

Project description:UHRF1 is essential for targeting DNA methyltransferases (DNMT’s) to replicating DNA to establish de novo DNA methylation and maintain it. While, UHRF1 domains are defined, including requirement for an E3 ligase region, for de novo methylation, those essential for maintenance have been difficult to outline. Herein, via a new assay, chromatin histone-binding and a hemimethylated DNA reader domains, but not the ligase domain are found essential for cancer-specific DNA methylation maintenance in human colorectal cancer (CRC) cells. Disrupting each essential domain phenocopies UHRF1 depletion for global DNA demethylation, reactivation of tumor suppressor genes (TSGs), and reduction in CRC invasion and metastatic properties. Moreover, there is strong negative correlation between high UHRF1 expression, low TSG expression, and abnormal methylation with CRC progression and overall survival. Our battery of findings suggest the value of targeting specific domains of UHRF1 for cancer therapy and adding a precision medicine approach through use of the biomarker associations we define.

2019-02-28 | GSE118970 | GEO

Defining UHRF1 Domains That Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties [expression]

2019-02-28 | GSE118971 | GEO

Defining UHRF1 Domains That Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties

Project description:Defining UHRF1 Domains That Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties

| PRJNA487589 | ENA

Defining UHRF1 Domains That Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties [expression]

Project description:Defining UHRF1 Domains That Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties [expression]

| PRJNA487596 | ENA

Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties.

Project description:UHRF1 facilitates the establishment and maintenance of DNA methylation patterns in mammalian cells. The establishment domains are defined, including E3 ligase function, but the maintenance domains are poorly characterized. Here, we demonstrate that UHRF1 histone- and hemimethylated DNA binding functions, but not E3 ligase activity, maintain cancer-specific DNA methylation in human colorectal cancer (CRC) cells. Disrupting either chromatin reader activity reverses DNA hypermethylation, reactivates epigenetically silenced tumor suppressor genes (TSGs), and reduces CRC oncogenic properties. Moreover, an inverse correlation between high UHRF1 and low TSG expression tracks with CRC progression and reduced patient survival. Defining critical UHRF1 domain functions and its relationship with CRC prognosis suggests directions for, and value of, targeting this protein to develop therapeutic DNA demethylating agents.

| S-EPMC6521721 | biostudies-literature

Defining UHRF1 Domains That Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-02-28 | GSE118972 | GEO

Hemi-methylated DNA regulates DNA methylation inheritance through allosteric control of H3 ubiquitylation by UHRF1

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

Non - canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cell

Project description:We have generated and validated degron alleles of UHRF1 and/or DNMT1 in several human colorectal cancer cell lines. We then used genomics and bioinformatics to precisely describe he DNA demethylation dynamics in these cells, leading to the conclusion that UHRF1 maintains DNA methylation in cancer cells not only by stimulating DNMT1. Proteomics and genetics lead us to conclude that UHRF1 regulates DNMT3A, DNMT3B and TET2 activity in addition to regulating DNMT1. The tools we have developed will be valuable for future research efforts, and our results advance our understanding of cancer epigenetics, with potentially important therapeutic applications.

2024-02-12 | PXD043254 | 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.

2024-12-02 | PXD049993 | Pride

Identificaiton of novel acetylation sites in UHRF1 mediated by acetyltransferase MOF

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.

2024-03-06 | PXD040426 | Pride

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