Multiple signalling pathways converge on UHRF1 stability and activity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA665250 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12699100.fastq.gz | Fastqsanger.gz | |||
| SRR12699101.fastq.gz | Fastqsanger.gz | |||
| SRR12699102.fastq.gz | Fastqsanger.gz | |||
| SRR12699103.fastq.gz | Fastqsanger.gz | |||
| SRR12699104.fastq.gz | Fastqsanger.gz |
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Project description:Propagation of DNA methylation through cell division relies on the recognition of methylated cytosines by UHRF1. We present an experimental system where regulation of global and site-specific demethylation can be dissected in great detail, which is part of the biology of stem cells transitioning to ground state pluripotency upon signal inhibition. In this study we begin to elucidate the signalling pathways that converge upon UHRF1 regulation by employing a high-throughput shRNA screen targeting genes of the mouse kinome, using UHRF1-GFP fluorescence as readout. Our screen identified a total of 251 genes, enriched in factors related to metabolic processes. We found that whilst all candidates tested rescued UHRF1 from proteasomal degradation, UHRF1 in Nags and Csnk2b knockdown prevented DNA methylation loss, whereas in Prpsap2 and Sephs2 knockdown cells UHRF1 activity was impaired leading to methylation loss. This study, therefore, provides a valuable resource for understanding the interface between signalling and its effect on the epigenome
2022-11-18 | GSE158453 | GEO
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
Project description:Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation with aberrant epigenetic alterations, leading joint destruction. However, epigenetic regulatory mechanisms underlying RA pathogenesis remain largely unknown. Here we showed that Ubiquitin-like containing PHD and RING finger domains 1 (known as UHRF1) is a central epigenetic regulator to suppressively orchestrate the expression of multiple exacerbation factors in RA. We found remarkable up-regulation of Uhrf1, which is known as a key molecular for maintenance of DNA methylation during cell division 1-3, in murine arthritis tissue, especially synovial fibroblasts (SF). SF-specific Uhrf1 conditional knockout mice indicated more severe arthritic phenotypes with apoptosis resistant SF. Integrative analysis between transcriptome and methylome showed that expression of several cytokines including Ccl20 were up-regulated in Uhrf1-deficient SF. In RA patients, disease activity scores, CCL20 expression, Th17 accumulation, apoptosis resistance were negatively correlated with UHRF1 expression in synovium. Finally, stabilization of UHRF1 by administration of Ryuvidine improved pathogenesis of arthritis model mice. Our results demonstrated that UHRF1 expressed in SF contributes to suppressively orchestrate expression of genes of multiple exacerbating factors under RA progression. Targeting UHRF1 could provide a novel therapeutic strategy for RA.
2021-02-16 | GSE166747 | GEO
Project description:Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation with aberrant epigenetic alterations, leading joint destruction. However, epigenetic regulatory mechanisms underlying RA pathogenesis remain largely unknown. Here we showed that Ubiquitin-like containing PHD and RING finger domains 1 (known as UHRF1) is a central epigenetic regulator to suppressively orchestrate the expression of multiple exacerbation factors in RA. We found remarkable up-regulation of Uhrf1, which is known as a key molecular for maintenance of DNA methylation during cell division 1-3, in murine arthritis tissue, especially synovial fibroblasts (SF). SF-specific Uhrf1 conditional knockout mice indicated more severe arthritic phenotypes with apoptosis resistant SF. Integrative analysis between transcriptome and methylome showed that expression of several cytokines including Ccl20 were up-regulated in Uhrf1-deficient SF. In RA patients, disease activity scores, CCL20 expression, Th17 accumulation, apoptosis resistance were negatively correlated with UHRF1 expression in synovium. Finally, stabilization of UHRF1 by administration of Ryuvidine improved pathogenesis of arthritis model mice. Our results demonstrated that UHRF1 expressed in SF contributes to suppressively orchestrate expression of genes of multiple exacerbating factors under RA progression. Targeting UHRF1 could provide a novel therapeutic strategy for RA.
2021-02-16 | GSE166746 | GEO
Project description:DNA methylation is an essential epigenetic regulation for cellular identity. In muscle stem cells, termed satellite cells, DNA methylation patterns are dynamically changed during muscle regeneration. However, how these DNA methylation patterns are maintained remain unclear. Here, we demonstrate that a key epigenetic regulator Uhrf1 (ubiquitin-like with PHD and RING finger domains 1) is activated in proliferating but not expressed in quiescent or differentiated satellite cells. Ablation of Uhrf1 in satellite cell impairs the proliferation and differentiation of satellite cells, leading to failure of muscle regeneration. Loss of Uhrf1 in satellite cells alters transcriptional programs and leads to DNA hypomethylation with the activation of Cdkn1a and Notch signalling. Down-regulation of Cdkn1a and Notch signalling rescued the proliferation and differentiation defect in Uhrf1-deficient satellite cells. Therefore, this study suggest that Uhrf1 can regulate the self-renewal and differentiation of satellite cells through DNA methylation patterning.
2022-02-04 | GSE169192 | GEO
Project description:DNA methylation is an essential epigenetic regulation for cellular identity. In muscle stem cells, termed satellite cells, DNA methylation patterns are dynamically changed during muscle regeneration. However, how these DNA methylation patterns are maintained remain unclear. Here, we demonstrate that a key epigenetic regulator Uhrf1 (ubiquitin-like with PHD and RING finger domains 1) is activated in proliferating but not expressed in quiescent or differentiated satellite cells. Ablation of Uhrf1 in satellite cell impairs the proliferation and differentiation of satellite cells, leading to failure of muscle regeneration. Loss of Uhrf1 in satellite cells alters transcriptional programs and leads to DNA hypomethylation with the activation of Cdkn1a and Notch signalling. Down-regulation of Cdkn1a and Notch signalling rescued the proliferation and differentiation defect in Uhrf1-deficient satellite cells. Therefore, this study suggest that Uhrf1 can regulate the self-renewal and differentiation of satellite cells through DNA methylation patterning.
2022-02-04 | GSE169184 | GEO
Project description:We used microarrays to explore the expression profile from cells expressing wild type and UHRF1 S674A mutant. HeLa cells expressing UHRF1 WT and S674A mutant showed similar gene expression pattern without significant affecting the transcription of DNA repari genes. UHRF1 was depleted in HeLa cells by shRNA treatment. Total RNA was purified and used to determine the global gene transcription profiles by microarray assays. The UHRF1-related genes expression profiles were compared among control cells, UHRF1-depleted cells, UHRF1 WT reconstituting cells and UHRF1 S674A mutant reconstituting cells.
2016-01-05 | E-GEOD-73751 | biostudies-arrayexpress
Project description:Deletion of Uhrf1 resulted in stage 1-specific defects during iNKT cell development. To investigate the molecular mechanism, we sorted WT and Uhrf1-KO stage 1 iNKT cells and performed RNA-seq. By comparing gene expression profile, we found metabolic defects in Uhrf1-KO stage 1 iNKT cells. The expression of CD71 (Tfrc), two subunits of CD98 (Slc3a2 and Slc7a5) and Glut3 (Slc2a3) was reduced in stage 1 iNKT cells. Besides, the downstream pathways of AKT-mTOR axis were significantly reduced. Collectively, our results suggest that Uhrf1 is required for iNKT cell development by regulating the Akt-mTOR signaling pathway. We first sorted WT and Uhrf1-KO stage 1 iNKT cells, extracted the mRNA and performed RNA-seq. We then analyzed the differentially expressed genes and performed KEGG pathway analysis. We used RT-PCR to verify the expression of the key nutrient related genes (Tfrc, Slc3a2, Slc7a5 and Slc2a3) and used flow cytometry to test the protein level of metabolic related molecules. Besides, we also analyzed the expression of genes of mTOR downstream pathways to demonstrate that Uhrf1 mediated AKt-mTOR axis regulates iNKT cell development.
2016-03-10 | E-GEOD-77941 | biostudies-arrayexpress
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 | GSE236026 | 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