Effect of depletion of UHRF1, DNMT1, DNMT3B during differentiation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE206742 | GEO | 2022/06/25
REPOSITORIES: GEO
Dataset's files
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Project description:Effect of depletion of UHRF1, DNMT1, DNMT3B during differentiation
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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.
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Project description:Accumulative studies indicate that DNA maintenance methylation by DNMT1 is initiated by binding of UHRF1 to replication fork. However, how UHRF1 gains access to chromatin in S phase is poorly understood. Here we report that LSH, a SNF2 family chromatin remodeler, facilitates DNA methylation in somatic cells primarily by promoting DNA methylation by DNMT1. We show that knockout of LSH in various somatic cells resulted in substantial reduction of DNA methylation, whereas knockout of DNMT3A and DNMT3B only moderately reduced the level of DNA methylation. Consistent with a role in maintenance methylation, genome-wide analysis of DNA methylation revealed a widespread reduction of DNA methylation in all genomic elements in LSH null cells. Mechanistically, we demonstrate that LSH interacts with UHRF1 but not DNMT1 and facilitates UHRF1 chromatin association, UHRF1-catalyzed H3 ubiquitination, and subsequent DNMT1 recruitment to replication fork. Notably, UHRF1 also enhances LSH association with replication fork. Thus, our study identifies LSH as an essential factor for maintenance methylation and provides novel insight into how LSH facilitates maintenance methylation.
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Project description:This methylation array was conducted to find out changes in genome-wide methylation pattern in THP-1 cells upon differentiation. Also, we tried to figure out the effects of knockdown of UHRF1, DNMT1 and DNMT3B in THP-1 cells in regulating genome-wide DNA methylation.
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Project description:Stable inheritance of DNA methylation is critical for maintaining the differentiated phenotypes in multicellular organisms. However, the molecular basis ensuring high fidelity of maintenance DNA methylation is largely unknown. Here, we demonstrate that two distinct modes of DNMT1 recruitment, one is DNA replication-coupled and the other is uncoupled mechanism, regulate the stable inheritance of DNA methylation. PCNA-associated factor 15 (PAF15) represents a primary target of UHRF1 and undergoes dual mono-ubiquitylation (PAF15Ub2) on chromatin. PAF15Ub2 specifically interacts with DNMT1 and controls the recruitment of DNMT1 in a DNA replication-coupled manner. Thus, loss of PAF15Ub2 results in impaired DNA methylation at sites replicating during early S phase. In contrast, outside of S phase or when PAF15 ubiquitylation is perturbed, UHRF1 ubiquitylates histone H3 to promote DNMT1 recruitment. Together, we identify replication-coupled and uncoupled mechanisms of maintenance DNA methylation, both of which collaboratively ensure the stable DNA methylation.
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Project description:Purpose: The goal of this study was to identify the gene expression profile of mouse retina which carries deletions in Dnmt1, Dnmt3a and Dnmt3b genes. Method: Retinal mRNA profiles of Postnatal day 15 wild type mice and Dnmt1, Dnmt3a and Dnmt3b mutant mice were generated by deep-sequencing
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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.
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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.
2024-03-06 | PXD040426 | Pride
Project description:DNA methylation is an essential epigenetic mark in mammals. It controls gene expression and genome stability. Global DNA methylation pattern is abnormal in cancers. Ubiquitin like with PHD and RING finger domains 1 (UHRF1) is a key epigenetic regulator that recruits and activates DNA methyltransferase 1 (DNMT1), the methylation maintenance enzyme. UHRF1 is a proven oncogene and its overexpression transforms cells in vitro and causes cancer in animal models. Therefore, UHRF1 provides a unique entry point into the links between epigenetics and cancer. However, it is still not fully clear how UHRF1 works in cancer cells. To understand UHRF1 functions in cancer, we employed experimental strategy to use an advanced chemical/genetic system, the auxin-inducible degron (AID) technology, whereby the degron-fused protein can be totally and rapidly degraded upon the addition of a small molecule, auxin. We chose the human CRC cell line HCT116 as our model and successfully generated UHRF1-AID and DNMT1-AID. Through this study, we made the significant discovery that UHRF1 not only regulates DNMT1, but also influences the activities of de novo methyltransferases DNMT3A and DNMT3B, as well as the active demethylase TET2.
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Project description:DNA methylation is an essential epigenetic mark in mammals. It controls gene expression and genome stability. Global DNA methylation pattern is abnormal in cancers. Ubiquitin like with PHD and RING finger domains 1 (UHRF1) is a key epigenetic regulator that recruits and activates DNA methyltransferase 1 (DNMT1), the methylation maintenance enzyme. UHRF1 is a proven oncogene and its overexpression transforms cells in vitro and causes cancer in animal models. Therefore, UHRF1 provides a unique entry point into the links between epigenetics and cancer. However, it is still not fully clear how UHRF1 works in cancer cells. To understand UHRF1 functions in cancer, we employed experimental strategy to use an advanced chemical/genetic system, the auxin-inducible degron (AID) technology, whereby the degron-fused protein can be totally and rapidly degraded upon the addition of a small molecule, auxin. We chose the human CRC cell line HCT116 as our model and successfully generated UHRF1-AID and DNMT1-AID. Through this study, we made the significant discovery that UHRF1 not only regulates DNMT1, but also influences the activities of de novo methyltransferases DNMT3A and DNMT3B, as well as the active demethylase TET2.
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