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UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma [epic_methyl]

ABSTRACT: Methylation array was performed to understand the role of UHRF1 in DNA methylation in KRAS mutant lung cancer cell lines. Knock-down of UHRF1 leads to significant changes in global DNA methylation in both cell lines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198446 | GEO | 2023/05/15

REPOSITORIES: GEO

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UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma [RNA-seq]

Project description:RNA sequening was performed to understand the role of UHRF1 in regulation of gene expression in KRAS mutant lung cancer cell lines. Knock-down of both UHRF1 and KRAS leads to significant and overlapping changes in gene expression in both cell lines.

2023-05-15 | GSE198289 | GEO

UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma [CRISPR_screen]

Project description:We performed a focused CRISPR in KRAS mutant lung cancer cells (A549) using a minipool sgRNA library targeting 80 lung cancer specific tumor suppressor genes and 12 control genes. This screen identified tumor suppressor genes regulated by Uhrf1 in KRAS mutant lung cancer.

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UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma [shRNA]

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UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma

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

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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

Ubiquitome analysis of UHRF1 and UHRF2-deficient mESCs

Project description:The E3 ligase UHRF1 is an essential epigenetic cofactor for DNMT1 dependent maintenance DNA methylation, which provides a binding platform for DNMT1 by both cooperative binding of histones and hemi-methylated DNA as well as by ubiquitinating histone H3. Here, we conduct a comprehensive screen to identify novel ubiquitination targets of UHRF1 and its paralogue UHRF2 by comparing the ubiquitome of wildtype (wt), UHRF1- and UHRF2-deficient mouse embryonic stem cells. With an antibody-dependent enrichment of ubiquitin remnant motif-containing peptides followed by isobaric-labeling based quantitative mass spectrometry, we find both known and novel E3 ligase substrates of UHRF1 involved in a variety of biological processes such as RNA processing, DNA methylation and DNA damage repair.

2017-10-24 | PXD006593 | Pride

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

Gene expression profiles of uhrf1 mutant zebrafish

Project description:UHRF1 (Ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 to hemimethylated DNA during replication, is essential for maintaining DNA methylation patterns during cell division and is suggested to direct additional repressive epigenetic marks. Uhrf1 mutation in zebrafish results in multiple embryonic defects including failed hepatic outgrowth, but the epigenetic basis of these phenotypes is not known. We find that DNA methylation is the only epigenetic mark that is depleted in uhrf1 mutants and make the surprising finding that despite the reduced organ size in uhrf1 mutants, genes regulating DNA replication and S-phase progression were highly upregulated. Further, there is a striking increase in BrdU incorporation in uhrf1 mutant cells, and they retained BrdU labeling over several days, indicating they are arrested in S-phase. Moreover, some of the label retaining nuclei co-localized with TUNEL positive nuclei, suggesting that arrested cells are responsible for apoptosis. Importantly, dnmt1 mutation phenocopies the S-phase arrest and hepatic outgrowth defects in uhrf1 mutants and Dnmt1 knock-down enhances the uhrf1 hepatic phenotype. Together, these data indicate that DNA hypomethylation is sufficient to generate the uhrf1 mutant phenotype by promoting an S-phase arrest. We thus propose that cell cycle arrest is a mechanism to restrict propagation of epigenetically deranged cells during embryogenesis. Genome-wide expression profiling was performed on 2 uhrf1 mutant and 2 wildtype zebrafish larvae (120 hours post fertilization) by using Zebrafish Genome Array (Affymetrix) according to manufacturer's instruction.

2015-02-09 | E-GEOD-55339 | biostudies-arrayexpress

Epigenome analyses of HCT116 cells stably expressing UHRF1 mutant [Illumina EPIC]

Project description:UHRF1 is a key regulator of DNA methylation maintenance. In this study, we investigated whether acetylation of UHRF1 affects its hemimethylated DNA binding affinity and alters genome-wide DNA methylation pattern. We show that cells with mutation in K490 of UHRF1 have distinct methylation profile versus wildtype UHRF1 expressing cells.

2020-06-06 | GSE151862 | GEO

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