Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1049452 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27118400_1.fastq.gz | Fastqsanger.gz | |||
| SRR27118400_2.fastq.gz | Fastqsanger.gz | |||
| SRR27118401_1.fastq.gz | Fastqsanger.gz | |||
| SRR27118401_2.fastq.gz | Fastqsanger.gz | |||
| SRR27118402_1.fastq.gz | Fastqsanger.gz |
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Project description:Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells
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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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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
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.
2024-02-12 | GSE249536 | GEO
Project description:DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease.
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Project description:Tumor-promoting functions of UHRF1 in retinoblastoma
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Project description:UHRF1 (ubiquitin-like with PHD and ring finger domains 1) is an epigenetic regulator that is involved in the regulation of DNA and histone methylation and many other cellular events. The UHRF1 is frequently found to be overexpressed in various human cancers including retinoblastoma, and its overexpression has been associated with tumor-promoting effects such as inhibition of apoptosis and high metastatic potential. However, the detailed mechanisms underlying these tumor-promoting functions of UHRF1 in retinoblastoma still remain unclear. In this study, we uncovered that UHRF1 depletion in retinoblastoma cells sensitizes the cells to histone deacetylase (HDAC) inhibitors, augmenting apoptotic cell death. To understand the molecular mechanisms underlying the enhanced sensitivity to HDAC inhibitors in the UHRF1-depleted retinoblastoma cells, we performed the gene expression profiling in UHRF1-knockdown Y79 cells in comparison with control-knockdown cells by RNA-sequencing to identify differentially expressed genes. Our RNA-seq results revealed that UHRF1 depletion downregulates redox-responsive genes such as GSTA4 and TXN2, leading to increased intracellular oxidative stress and higher susceptibility to HDAC inhibitor treatment.
2020-02-10 | GSE135424 | GEO
Project description:UHRF1 (ubiquitin-like with PHD and ring finger domains 1) is an epigenetic regulator that is involved in the regulation of DNA and histone methylation and many other cellular events. The UHRF1 is frequently found to be overexpressed in various human cancers, and its overexpression has been associated with pro-tumorigenic effects such as inhibition of apoptosis and high metastatic potential. However, the molecular mechanisms underlying these pro-tumorigenic effects of UHRF1 overexpression in cancers still remain unclear. Retinoblastoma (Rb) is an intraocular tumor which arises from developing retina by biallelic inactivation of Rb1 gene. In this study, we uncovered that the UHRF1 is highly expressed in retinoblastoma, and genomes of retinoblastoma have differential DNA methylation patterns compared to those of normal retina, characterized by global hypomethylation and promoter hypermethylation at key tumor suppressor genes. Given the well-documented functions of UHRF1 in the regulation of DNA methylation, we hypothesized that the overexpressed UHRF1 may contribute to the aberrant DNA methylation in retinoblastoma genomes. To test our hypothesis, we profiled the genome-wide methylation patterns in normal retina and Y79 retinoblastoma cell line by MeDIP-seq, and then investigated how the methylation patterns in Y79 are affected by down-modulation of UHRF1. For identification of differentially methylated regions between the control and UHRF1 knockdown Y79 cells, we analysed three independent sets of sequencing data to unambiguously determine the effects of UHRF1 down-modulation on the methylome of Y79 retinoblastoma cells.
2017-03-30 | GSE92712 | GEO
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:Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific cell lineage, changes in histone modifications and DNA methylation accompany the transition to more specialized cell types. Investigating how epigenetic regulation maintains pluripotency is a critical component in order to generate the required cell types for future clinical application. Uhrf1 is a widely known hemi-methylated DNA binding protein, playing a role in heterochromatin formation alongside G9a, Trim28 and HDACs. In addition, it has been demonstrated that Uhrf1 functions to maintain DNA methylation through the recruitment of Dnmt1. Although Uhrf1 is not essential in ESC self-renewal, it still remains elusive how Uhrf1 regulates pluripotency. Here, we set out to elucidate the role of Uhrf1 in pluripotent stem cells. We found that Uhrf1 forms a complex with the active trithorax group of transcriptional regulators, in particular the Setd1a/COMPASS complex. Our data show that loss of Uhrf1 causes a dramatic reduction of bivalent histone marks, in particular those associated with neuroectoderm and mesoderm specification. Overall, our data demonstrate that Uhrf1 safeguards the balance between pluripotency and differentiation via the Setd1a/COMPASSS complex, through which Uhrf1 mediates bivalent histone modifications.
2018-05-02 | GSE113912 | GEO