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The maintenance of epigenetic characteristics is essential for the normal growth and development of organisms. The maintenance of DNA methylation is an important way to maintain the epigenetic characteristics of organisms. DNMT1 is a core enzyme that maintains intracellular DNA methylation, and UHRF1, as a cofactor of DNMT1, plays an important role in the regulation of DNA methylation by DNMT1. The maintenance of DNA methylation mediated by UHRF1–DNMT1 complex is involved in the regulation of many vital activities. This review describes the whole molecular process of UHRF1–DNMT1 pathway from the opening of inhibitory structure to the end of maintenance methylation in detail and lists some latest biological research progress related to this pathway in the development of early embryonic, maintenance of pluripotency of embryonic stem cells, regulation of expression of imprinted genes, inactivation of X chromosome, and development of cancer. Finally, put forward some problems remained to be solved at present and new thoughts. [ABSTRACT FROM AUTHOR]

Background: Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is upregulated in colon cancer cells and associated with silencing tumor suppressor genes (TSGs) to promote colon cancer cell proliferation. Objective: To investigate epigenetic modification of UHRF1 by TIP60. Whether UHRF1 acetylation by TIP60 can induce cell proliferation in colon cancer cells. Methods: Acetylation sites of UHRF1 by TIP60 was predicted by ASEB (Acetylation Set Enrichment Based) method and identified by immunoprecipitation assay using anti-pan-acetyl lysine antibody and in vitro acetylation assay. Based on this method, UHRF1 acetylation-deficient mimic 4KR (K644R, K646R, K648R, K650R) mutant was generated to investigate effects of UHRF1 acetylation by TIP60. shRNA system was used to generate stable knockdown cell line of UHRF1. With transient transfection of UHRF1 WT and 4KR, the effects of UHRF1 4KR mutant on Jun dimerization protein 2 (JDP2) gene expression, cell proliferation and cell cycle were investigated by RT-qPCR and FACS analysis in shUHRF1 colon cancer cell line. Results: Downregulation of TIP60-mediated UHRF1 acetylation is correlated with suppressed cell cycle progression. Acetylation-deficient mimic of UHRF1 showed poor cell growth through increased expression of JDP2 gene. Conclusions: Acetylation of UHRF1 4K residues by TIP60 is important for colon cancer cell growth. Furthermore, upregulated JDP2 expression by acetylation-deficient mutant of UHRF1 might be an important epigenetic target for colon cancer cell proliferation. [ABSTRACT FROM AUTHOR]

UHRF1 (Ubiquitin-like with PHD and Ring Finger domains 1) is a crucial E3 ubiquitin ligase and epigenetic regulator with pivotal roles in various biological processes, including the maintenance of DNA methylation, regulation of gene expression, and facilitation of DNA damage repair. In this study, we unveil that UHRF1 interacts with the nonhomologous end joining factor XLF (also known as Cernunnos) following DNA double strand breaks in HeLa cells. Furthermore, we demonstrate that UHRF1 catalyzes lysine 63-linked polyubiquitination of XLF, rather than lysine 48-linked polyubiquitination. Notably, this polyubiquitination of XLF by UHRF1 does not affect its protein stability; instead, it enhances the recruitment of XLF to the sites of DNA damage. These findings shed light on the role of UHRF1 as a novel regulator of DNA repair through XLF in tumor cells., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interests with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Epigenetic regulatory mechanisms are divergent across the animal kingdom, yet these mechanisms are not well studied in non-model organisms. Unique features of cephalopods make them attractive for investigating behavioral, sensory, developmental, and regenerative processes, and recent studies have elucidated novel features of genome organization and gene and transposon regulation in these animals. However, it is not known how epigenetics regulates these interesting cephalopod features. We combined bioinformatic and molecular analysis of Octopus bimaculoides to investigate the presence and pattern of DNA methylation and examined the presence of DNA methylation and 3 histone post-translational modifications across tissues of three cephalopod species. Results: We report a dynamic expression profile of the genes encoding conserved epigenetic regulators, including DNA methylation maintenance factors in octopus tissues. Levels of 5-methyl-cytosine in multiple tissues of octopus, squid, and bobtail squid were lower compared to vertebrates. Whole genome bisulfite sequencing of two regions of the brain and reduced representation bisulfite sequencing from a hatchling of O. bimaculoides revealed that less than 10% of CpGs are methylated in all samples, with a distinct pattern of 5-methyl-cytosine genome distribution characterized by enrichment in the bodies of a subset of 14,000 genes and absence from transposons. Hypermethylated genes have distinct functions and, strikingly, many showed similar expression levels across tissues while hypomethylated genes were silenced or expressed at low levels. Histone marks H3K27me3, H3K9me3, and H3K4me3 were detected at different levels across tissues of all species. Conclusions: Our results show that the DNA methylation and histone modification epigenetic machinery is conserved in cephalopods, and that, in octopus, 5-methyl-cytosine does not decorate transposable elements, but is enriched on the gene bodies of highly expressed genes and could cooperate with the histone code to regulate tissue-specific gene expression. [ABSTRACT FROM AUTHOR]

Background: LncRNA ubiquitin-like with PHD and RING finger domains 1 (UHRF1) protein associated transcript (UPAT) regulates the progression of many cancers. However, its role in gastric cancer (GC) is less frequently reported. Objective: In the context of the promoting effect of lncRNA on modulating GC progression, detailed insights into the role and underlying mechanism of UPAT in GC are the foothold in this study. Methods: Overall survival was calculated. The mRNA expressions of UPAT and UHRF1 were measured by qRT-PCR, and the protein expressions of UHRF1, Cyclin D1 and cleaved caspase-3 were determined by western blot. Cell viability, growth, migration and invasion were assessed by CCK-8, colony formation, wound healing and Transwell assays, respectively. Apoptosis rate and cell cycle were assayed by flow cytometry. Results: UPAT was overexpressed in GC tissue and cell lines. Decreased UPAT level was associated with higher overall survival. Down-regulation of UPAT diminished cell proliferation, Cyclin D1 expression, and migration and invasion rates, increased apoptosis rate and cleaved caspase-3 expression, and blocked cell cycle in AGS and NCI-N87 cells. UPAT expression in GC was positively correlated with UHRF1 expression. UHRF1 overexpression offset the inhibitory effects of UPAT down-regulation on cell proliferation, migration, invasion and cell cycle, and partially reversed the positive effect of UPAT down-regulation on apoptosis. Conclusion: UPAT might positively regulate the progression of GC via interacting with UHRF1. The UHRF1/UPAT axis revealed in the present study may provide a promising approach to intervene in the progression of GC. [ABSTRACT FROM AUTHOR]

Simple Summary: We provided evidence that ubiquitin-like, containing PHD and RING finger domain, 1 (UHRF1) is overexpressed in acute lymphocytic leukemia (ALL). We further showed that UHRF1 directly interacts and regulates c-Myc expression to enable ALL cell growth through the cMYC-CDK4/6 phosphoRb-signaling axis. Ubiquitin-like, containing PHD and RING finger domain, (UHRF) family members are overexpressed putative oncogenes in several cancer types. We evaluated the protein abundance of UHRF family members in acute leukemia. A marked overexpression of UHRF1 protein was observed in ALL compared with AML. An analysis of human leukemia transcriptomic datasets revealed concordant overexpression of UHRF1 in B-Cell and T-Cell ALL compared with CLL, AML, and CML. In-vitro studies demonstrated reduced cell viability with siRNA-mediated knockdown of UHRF1 in both B-ALL and T-ALL, associated with reduced c-Myc protein expression. Mechanistic studies indicated that UHRF1 directly interacts with c-Myc, enabling ALL expansion via the CDK4/6-phosphoRb axis. Our findings highlight a previously unknown role of UHRF1 in regulating c-Myc protein expression and implicate UHRF1 as a potential therapeutic target in ALL. [ABSTRACT FROM AUTHOR]

DNA methylation and histone lysine tri-methylation at H3K27 (H3K27me3) are two chromatin modifications for transcriptional gene silencing, which play important roles in diverse biological processes, including cell fate determination and cell lineage commitment. These two marks are largely mutually exclusive and target distinct sets of genes in the mammalian genome. However, how H3K27me3 shapes the DNA methylome remains elusive. Here, we report that the loss of H3K27me3 modification leads to increased DNA methylation at previously marked H3K27me3 sites, indicating that H3K27me3 negatively regulates DNA methylation. Genome-wide analysis of H3 ubiquitination, essential for recruitment and activation of DNA methyltransferase DNMT1, reveals the absence of H3 ubiquitination at H3K27me3 marked nucleosomes. Moreover, loss of H3K27me3 modification induces an increase in H3K18 ubiquitination at the corresponding hyper-methylated loci. Importantly, we show that H3K27me3 directly inhibits UHRF1-mediated H3 ubiquitination toward nucleosomes in a defined biochemical assay. Taken together, our findings reveal a general mechanism for H3K27me3-mediated shaping of the mammalian DNA methylome via modulation of H3 ubiquitination. [ABSTRACT FROM AUTHOR]

Ubiquitin-like containing plant homeodomain Ring Finger 1 (UHRF1) protein is recognized as a cell-cycle-regulated multidomain protein. UHRF1 importantly manifests the maintenance of DNA methylation mediated by the interaction between its SRA (SET and RING associated) domain and DNA methyltransferase-1 (DNMT1)-like epigenetic modulators. However, overexpression of UHRF1 epigenetically responds to the aberrant global methylation and promotes tumorigenesis. To date, no potential molecular inhibitor has been studied against the SRA domain. Therefore, this study focused on identifying the active natural drug-like candidates against the SRA domain. A comprehensive set of in silico approaches including molecular docking, molecular dynamics (MD) simulation, and toxicity analysis was performed to identify potential candidates. A dataset of 709 natural compounds was screened through molecular docking where chicoric acid and nystose have been found showing higher binding affinities to the SRA domain. The MD simulations also showed the protein ligand interaction stability of and in silico toxicity analysis has also showed chicoric acid as a safe and nontoxic drug. In addition, chicoric acid possessed a longer interaction time and higher LD50 of 5000 mg/kg. Moreover, the global methylation level (%5 mC) has been assessed after chicoric acid treatment was in the colorectal cancer cell line (HCT116) at different doses. The result showed that 7.5 pM chicoric acid treatment reduced methylation levels significantly. Thus, the study found chicoric acid can become a possible epidrug-like inhibitor against the SRA domain of UHRF1 protein. [ABSTRACT FROM AUTHOR]

The ubiquitination process, which involves that binding of an ubiquitin protein to certain substrates, regulates several human biological processes and human cancers. Several studies report that the abnormal expression of quite a few E3 ubiquitin ligases could play critical role in carcinogenic process and cancer progression. In our current study, we identify UHRF1 (Ubiquitin Like with PHD And Ring Finger Domain 1) is an important regulator for breast cancer growth. UHRF1 depletion significantly decreases breast cancer growth in vitro and in vivo. Clinical data analysis reveals that UHRF1 is dramatically elevated in breast cancer, compared to normal breast tissue. UHRF1 correlates with poor survival in luminal type of breast cancer patients, but not in ER-negative groups. The molecular biological studies show that UHRF1 localizes in the nuclear and interact with ERα via its SRA domain, which subsequently inhibits K48-linked ubiquitination of ERα and enhances ERα stability. Our study provides a novel function of UHRF1 in regulation estrogen signaling in breast cancer and a promising target for breast cancer therapeutics. [ABSTRACT FROM AUTHOR]

Danfeng Li,1,&ast; Binlie Chen,1,2,&ast; Yongming Zeng,1,&ast; Huaiming Wang1 1Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, People’s Republic of China; 2Medical college, Shantou University, Shantou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huaiming WangDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, 57 Changping Road, Shantou, 515041, People’s Republic of ChinaTel +86 13750417745Fax +86 0754-88259850Email 13750417745@163.comObjective: This study was performed to investigate the relationship among UHRF1 expression, its biological function and immune infiltration in human hepatocellular carcinoma (HCC).Methods: Gene Expression Profiling Interactive Analysis (GEPIA), Oncomine, and The Cancer Genome Atlas (TCGA) databases were used to analyze UHRF1 expression between HCC and normal tissues. Subsequently, GEPIA, TCGA-Portal, Kaplan–Meier Plotter, Protein Atlas and SurvExpress databases were utilized for survival analysis. UHRF1 co-expression genes were identified via the cBioPortal and LinkedOmics databases. Further, gene ontology (GO) analysis as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed. Protein–protein interaction (PPI) networks was constructed by STRING database and Cytoscape 3.7.1. Single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT algorithm were employed to assess the correlation between UHRF1 and tumor immune infiltrates on TCGA database. TIMER 2.0 database was used to explore the correlation of UHRF1 expression and immune infiltration level in HCC. Additionally, RT-qPCR was used to analyze the expression of UHRF1 and the relative genes in HCC cell lines.Results: Expression level of UHRF1 was upregulated in HCC tissues compared with paired normal tissues (P < 0.05 in GEPIA; P = 1.78E− 6 in Oncomine; and P < 0.0001 in TCGA). Its high expression was significantly related with a shorter overall survival in five databases (P < 0.05). Function enrichment analysis demonstrated that functions of UHRF1 concentrated in cell division process and cell cycle (P < 0.05). High UHRF1 expression exhibited dysregulated immune infiltration (ie, neutrophils, eosinophils, dendritic cells resting, macrophages M2, macrophages M0) and poor survival of high UHRF1 expression was tight correlated with immune infiltration status. Moreover, TP53 mutation can lead to high expression of UHRF1 (P = 4.2E− 10).Conclusion: UHRF1 might function as an oncogene via inducing dysregulated immune infiltration in HCC and was identified as a novel prognostic biomarker and potential therapeutic target for HCC.Keywords: UHRF1, biomarker, prognosis, immune infiltrates, HCC

Abstract Background Age-associated changes attenuate human blood system functionality through the aging of hematopoietic stem and progenitor cells (HSPCs), manifested in human populations an increase in myeloproliferative disease and even leukemia; therefore, study on HSPC senescence bears great significance to treat hematopoietic-associated disease. Furthermore, the mechanism of HSPC aging is lacking, especially the cellular memory mechanism. Here, we not only reported a new HSPC senescence model in vitro, but also propose and verify the cellular memory mechanism of HSPC aging of the Polycomb/Trithorax system. Methods HSPCs (Lin−c-kit+ cells) were isolated and purified by magnetic cell sorting (MACS). The proportions and cell cycle distribution of cells were determined by flow cytometry; senescence-related β-galactosidase assay, transmission electron microscope (TEM), and colony-forming unit (CFU)-mix assay were detected for identification of the old HSPC model. Proteomic tests and RNA-seq were applied to analyze differential pathways and genes in the model cells. qPCR, Western blot (WB), and chromatin immunoprecipitation PCR (CHIP-PCR) were used to detect the gene expression of cell memory-related proteins. Knockdown of cell memory-related key genes was performed with shRNA interference. Results In the model old HSPCs, β-gal activity, cell cycle, colony-forming ability, aging-related cell morphology, and metabolic pathway were significantly changed compared to the young HSPCs. Furthermore, we found the model HSPCs have more obvious aging manifestations than those of natural mice, and IL3 is the major factor contributing to HSPC aging in the model. We also observed dramatic changes in the expression level of PRC/TrxG complexes. After further exploring the downstream molecules of PRC/TrxG complexes, we found that Uhrf1 and TopII played critical roles in HSPC aging based on the HSPC senescence model. Conclusions These findings proposed a new HSPC senescence model in vitro which we forecasted could be used to preliminary screen the drugs of the HSPC aging-related hemopathy and suggested cellular memory mechanism of HSPC aging.

Ubiquitin-like containing plant homeodomain Ring Finger 1 (UHRF1) protein is recognized as a cell-cycle-regulated multidomain protein. UHRF1 importantly manifests the maintenance of DNA methylation mediated by the interaction between its SRA (SET and RING associated) domain and DNA methyltransferase-1 (DNMT1)-like epigenetic modulators. However, overexpression of UHRF1 epigenetically responds to the aberrant global methylation and promotes tumorigenesis. To date, no potential molecular inhibitor has been studied against the SRA domain. Therefore, this study focused on identifying the active natural drug-like candidates against the SRA domain. A comprehensive set of in silico approaches including molecular docking, molecular dynamics (MD) simulation, and toxicity analysis was performed to identify potential candidates. A dataset of 709 natural compounds was screened through molecular docking where chicoric acid and nystose have been found showing higher binding affinities to the SRA domain. The MD simulations also showed the protein ligand interaction stability of and in silico toxicity analysis has also showed chicoric acid as a safe and nontoxic drug. In addition, chicoric acid possessed a longer interaction time and higher LD50 of 5000 mg/kg. Moreover, the global methylation level (%5 mC) has been assessed after chicoric acid treatment was in the colorectal cancer cell line (HCT116) at different doses. The result showed that 7.5 µM chicoric acid treatment reduced methylation levels significantly. Thus, the study found chicoric acid can become a possible epidrug-like inhibitor against the SRA domain of UHRF1 protein.

Beina Hui,1 Shupei Pan,2 Shaomin Che,1 Yuchen Sun,1 Yanli Yan,1 Jia Guo,1 Tuotuo Gong,1 Juan Ren,1 Xiaozhi Zhang1 1Department of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, People’s Republic of China; 2Department of Radiation Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710004, People’s Republic of ChinaCorrespondence: Juan Ren; Xiaozhi Zhang Tel +86 2985324029; +86 2985324621Email 869491533@qq.com; zhangxiaozhi@xjtu.edu.cnPurpose: Resistance to radiotherapy results in a high treatment failure rate for locally advanced esophageal squamous cell carcinoma (ESCC). Ubiquitin-like with plant homeodomain and ring-finger domains 1 (UHRF1), is associated with poor prognosis in ESCC. The present study aims to characterize the effect of UHRF1 silencing on the radiosensitivity of ESCC and its potential mechanism.Methods: Both in vitro and in vivo experiments were conducted to observe the effects of UHRF1 silencing on the radiosensitivity of ESCC. The effects of UHRF1 silencing on the apoptosis of ESCC cells were assessed by flow cytometry. The expression of apoptosis-related factors (caspase-3 and Bcl-2), PI3K/Akt/mTOR signaling pathway-related factors (PTEN, p-Akt and Akt, p-mTOR and mTOR), and DNMT1 were measured via Western blot, and the status of PTEN methylation was detected by methylation-specific PCR. Immunohistochemistry was used to detect the expressions of PTEN, p-AKT, and p-mTOR in xenograft tumor tissues.Results: In vitro and in vivo experiments showed that UHRF1 knock-down inhibited ESCC cell growth and enhanced their radiosensitivity. shUHRF1 combined with radiation significantly increased ESCC cell apoptosis. Meanwhile, it activated the expression of caspase-3 and inhibited the expression of Bcl-2. shUHRF1 inhibited the expression of DNMT1 and reduced the methylation of PTEN, and then upregulated the expression of PTEN to inhibit the PI3K/Akt/mTOR signaling pathway. On the contrary, the PI3K/Akt/mTOR signaling pathway can be activated by upregulation of UHRF1.Conclusion: Our findings provide a theoretical basis for UHRF1 as a target to improve the radiosensitivity of ESCC.Keywords: radiosensitivity, UHRF1, esophageal squamous carcinoma, shRNA, PI3K/Akt/mTOR

Genome instability is one of the leading causes of gastric cancers. However, the mutational landscape of driver genes in gastric cancer is poorly understood. Here, we investigate somatic mutations in 25 Korean gastric adenocarcinoma patients using whole‐exome sequencing and show that PWWP2B is one of the most frequently mutated genes. PWWP2B mutation correlates with lower cancer patient survival. We find that PWWP2B has a role in DNA double‐strand break repair. As a nuclear protein, PWWP2B moves to sites of DNA damage through its interaction with UHRF1. Depletion of PWWP2B enhances cellular sensitivity to ionizing radiation (IR) and impairs IR‐induced foci formation of RAD51. PWWP2B interacts with MRE11 and participates in homologous recombination via promoting DNA end‐resection. Taken together, our data show that PWWP2B facilitates the recruitment of DNA repair machinery to sites of DNA damage and promotes HR‐mediated DNA double‐strand break repair. Impaired PWWP2B function might thus cause genome instability and promote gastric cancer development. Synopsis: PWWP2B moves to sites of DNA damage through its interaction with UHRF1 and promotes end‐resection by recruiting MRE11 to DNA lesions. PWWP2B is mutated in eight out of 25 Korean STAD patients.PWWP2B interacts with UHRF1 and MRE11.Depletion of PWWP2B decreases IR‐induced MRE11, Rad51, RPA2 foci, leading to impairment of DNA end‐resection and HR. [ABSTRACT FROM AUTHOR]

Nigella sativa oil, commonly known as black seed oil (BSO), is a well-known Mediterranean food, and its consumption is associated with beneficial effects on human health. A large number of BSO's therapeutic properties is attributed to its pharmacologically active compound, thymoquinone (TQ), which inhibits cell proliferation and induces apoptosis by targeting several epigenetic players, including the ubiquitin-like, containing plant homeodomain (PHD) and an interesting new gene, RING finger domains 1 (UHRF1), and its partners, DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1). This study was designed to compare the effects of locally sourced BSO with those of pure TQ on the expression of the epigenetic complex UHRF1/DNMT1/HDAC1 and the related events in several cancer cells. The gas chromatographs obtained from GC-MS analyses of extracted BSO showed that TQ was the major volatile compound. BSO significantly inhibited the proliferation of MCF-7, HeLa and Jurkat cells in a dose-dependent manner, and it induced apoptosis in these cell lines. BSO-induced inhibitory effects were associated with a significant decrease in mRNA expression of UHRF1, DNMT1 and HDAC1. Molecular docking and MD simulation showed that TQ had good binding affinity to UHRF1 and HDAC1. Of note, TQ formed a stable metal coordinate bond with zinc tom, found in the active site of the HDAC1 protein. These findings suggest that the use of TQ-rich BSO represents a promising strategy for epigenetic therapy for both solid and blood tumors through direct targeting of the trimeric epigenetic complex UHRF1/DNMT1/ HDAC1. [ABSTRACT FROM AUTHOR]

Summary: Background: The multiplicity, heterogeneity, and dynamic nature of human immunodeficiency virus type-1 (HIV-1) latency mechanisms are reflected in the current lack of functional cure for HIV-1. Accordingly, all classes of latency-reversing agents (LRAs) have been reported to present variable ex vivo potencies. Here, we investigated the molecular mechanisms underlying the potency variability of one LRA: the DNA methylation inhibitor 5-aza-2’-deoxycytidine (5-AzadC). Methods: We employed epigenetic interrogation methods (electrophoretic mobility shift assays, chromatin immunoprecipitation, Infinium array) in complementary HIV-1 infection models (latently-infected T-cell line models, primary CD4+ T-cell models and ex vivo cultures of PBMCs from HIV+ individuals). Extracellular staining of cell surface receptors and intracellular metabolic activity were measured in drug-treated cells. HIV-1 expression in reactivation studies was explored by combining the measures of capsid p24Gag protein, green fluorescence protein signal, intracellular and extracellular viral RNA and viral DNA. Findings: We uncovered specific demethylation CpG signatures induced by 5-AzadC in the HIV-1 promoter. By analyzing the binding modalities to these CpG, we revealed the recruitment of the epigenetic integrator Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) to the HIV-1 promoter. We showed that UHRF1 redundantly binds to the HIV-1 promoter with different binding modalities where DNA methylation was either non-essential, essential or enhancing UHRF1 binding. We further demonstrated the role of UHRF1 in the epigenetic repression of the latent viral promoter by a concerted control of DNA and histone methylations. Interpretation: A better understanding of the molecular mechanisms of HIV-1 latency allows for the development of innovative antiviral strategies. As a proof-of-concept, we showed that pharmacological inhibition of UHRF1 in ex vivo HIV+ patient cell cultures resulted in potent viral reactivation from latency. Together, we identify UHRF1 as a novel actor in HIV-1 epigenetic silencing and highlight that it constitutes a new molecular target for HIV-1 cure strategies. Funding: Funding was provided by the Belgian National Fund for Scientific Research (F.R.S.-FNRS, Belgium), the « Fondation Roi Baudouin », the NEAT (European AIDS Treatment Network) program, the Internationale Brachet Stiftung, ViiV Healthcare, the Télévie, the Walloon Region (« Fonds de Maturation »), « Les Amis des Instituts Pasteur à Bruxelles, asbl », the University of Brussels (Action de Recherche Concertée ULB grant), the Marie Skodowska Curie COFUND action European Union's Horizon 2020 research and innovation program under grant agreement No 691119-EU4HIVCURE-H2020-MSCA-RISE-2015, the French Agency for Research on AIDS and Viral Hepatitis (ANRS), the Sidaction and the “Alsace contre le Cancer” Foundation. This work is supported by 1UM1AI164562-01, co-funded by National Heart, Lung and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute on Drug Abuse and the National Institute of Allergy and Infectious Diseases.

Trophoblasts play critical roles in establishment and maintenance of a normal pregnancy. Their dysfunction in early pregnancy is closely related to pregnancy‐related diseases, including recurrent pregnancy loss (RPL). Epigenetic modifications dynamically change during pregnancy; however, the role of the epigenetic modifier UHRF1 in trophoblast regulation remains unknown. This is the first study to show that UHRF1 expression was localized in the cytoplasm of cytotrophoblasts, syncytiotrophoblasts, and villi columns, and decreased in the villi of patients with RPL. The invasion and cell viability in a UHRF1 knockdown trophoblast cell line were significantly decreased. In addition, the mRNA expression profiles of Swan71 cells were partially altered by UHRF1 knockdown. The altered immune‐related genes were screened out and the pro‐inflammatory TH1‐type chemokine/cytokines CXCL2 and IL‐1β were identified as the most promising targets of UHRF1 in the trophoblasts, which were significantly increased in the UHRF1 knockdown Swan71 cells, villi, and serum from patients with RPL. The macrophages treated with the supernatants of UHRF1 knockdown Swan71 cells were polarized to the M1 phenotype and secreted high levels of pro‐inflammatory cytokines, which might be driven by the activated MyD88/NF‐κB signaling pathway and mediated by the increased expression of CXCR2 and IL‐1R1 (CXCL2 and IL‐1β receptors, respectively). In addition, the supernatants of UHRF1 knockdown Swan71 cells showed stronger chemotaxis to macrophages than those from the controls. Our findings highlight the previously unknown roles of UHRF1 as one of the key regulators on the trophoblasts and their cross‐talk with local immune cells, and demonstrate a potential approach for RPL intervention. [ABSTRACT FROM AUTHOR]

Abstract Objectives UHRF1 is a multi-domain protein that recognizes both histone and DNA modification marks on chromatin. UHRF1 is involved in various cellular processes that lead to tumorigenesis and thus attracted considerable attention as a potential anti-cancer drug target. The SRA domain is a unique to the UHRF family. SRA domain recognizes 5-methylcytosine in hemimethylated DNA and necessary for maintenance DNA methylation mediated by DNMT1. Small molecules capable of interacting with the SRA domain may reduce aberrant methylation levels by preventing the interaction of 5-methylcytosine with the SRA domain and thereby blocking substrate access to the catalytic center of DNMT1. The data were collected to identify and predict an initial set of small molecules that are expected to bind to the SRA domain. Data description Nearly 2.4 million molecules from various chemical libraries were screened with the SRA domain of UHRF1 using Schrodinger’s Small Molecule Drug Discovery Suite. The data is available in the form of a methodology presentation, MS Excel files listing the top hits, and Maestro pose viewer files that provide visualization of how the identified ligands interact with the SRA domain.

Abstract Background Current therapies for multiple myeloma (MM) are associated with toxicity and resistance, highlighting the need for novel effective therapeutics. Berberine (BBR), a botanical alkaloid derived from several Berberis medicinal plants, has exhibited anti-tumor effects, including against multiple myeloma (MM); however, the molecular mechanism underlying the anti-MM effect has not been previously described. This study aimed to identify the target of berberine and related mechanisms involved in its therapeutic activity against MM. Results Here, we demonstrated that BBR treatment killed MM cells in vitro and prolonged the survival of mice bearing MM xenografts in vivo. A screening approach integrating surface plasmon resonance (SPR) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified UHRF1 (ubiquitin-like with PHD and RING Finger domains 1) as a potential target of BBR. Combining molecular docking and SPR analysis, we confirmed UHRF1 as a BBR-binding protein and discovered that BBR binds UHRF1 in the tandem tudor domain and plant homeodomain (TTD-PHD domain). BBR treatment induced UHRF1 degradation via the ubiquitin-dependent proteasome system and reactivated p16INK4A and p73 in MM cells. Overexpression of UHRF1 promoted the MM cell proliferation and rendered MM cells more resistant to BBR, while silencing of UHRF1 with siRNA attenuated BBR-induced cytotoxicity. Conclusions In summary, our study has identified UHRF1 as a direct target of BBR and uncovered molecular mechanisms involved in the anti-MM activity of BBR. Targeting UHRF1 through BBR may be a novel therapeutic strategy against MM.

Identification of new genetic pathways or molecular targets that sensitize cancer cells to chemotherapeutic drugs may improve the efficacy of current chemotherapy. Here, we report that downmodulation of UHRF1 (ubiquitin‐like with PHD and RING finger domains 1) in retinoblastoma (RB) cells increases the sensitivity to histone deacetylase (HDAC) inhibitors, augmenting apoptotic cell death. We found that UHRF1 depletion downregulates two redox‐responsive genes GSTA4 (glutathione S‐transferase α4) and TXN2 (thioredoxin‐2) in RB cells, and increases the basal level of intracellular oxidative stress. Antioxidant treatment significantly reduced both basal and HDAC inhibitor‐induced DNA damage and apoptosis in UHRF1‐depleted cells. Knockdown of GSTA4 or TXN2 sensitized RB cells to HDAC inhibitors, demonstrating that GSTA4 and TXN2 play key roles in redox homeostasis in RB cells and the susceptibility to HDAC inhibitor treatment upon UHRF1 depletion. In human primary RB, GSTA4 and TXN2 proteins were found to be mostly elevated along with high UHRF1 expression. In addition to augmentation of apoptosis in UHRF1‐depleted RB cells, we also show that UHRF1 downmodulation derepresses the expression of photoreceptor‐specific genes in RB cells in cooperation with a HDAC inhibitor MS‐275 and promotes neuron‐like differentiation. However, further investigation revealed that the enhanced growth‐inhibitory effects of MS‐275 in UHRF1‐depleted cells were still mainly due to robust apoptosis induction rather than differentiation‐mediated growth arrest. Consistent with our findings, UHRF1 depletion in RB cells increased the therapeutic efficacy of MS‐275 in murine orthotopic xenografts. These results provide a novel basis for potential benefits of UHRF1 targeting for RB treatment.

Uhrf1 is a multi-domain and multifunctional epigenetic regulator playing key roles in DNA methylation, cell metabolism, and cell proliferation. To investigate the role of Uhrf1 in the reproductive physiology of female yaks, we collected three reproductive organs (ovaries, oviducts, and uteri) from healthy yaks during three reproductive phases (follicular, luteal, and gestational phases), with a total of nine groups. Real-time fluorescence quantitative PCR (RT-qPCR), Western blotting, and immunohistochemistry (IHC) were employed to determine the expression levels of Uhrf1 and the subcellular localization of this protein. RT-qPCR and Western blotting results showed that Uhrf1 was expressed highest in the oviduct during the follicular phase, moderate expression in the uterus during the gestational phase, and the lowest expression in the uterus during the luteal phase ( P < 0.05). IHC results showed that Uhrf1 was mainly expressed in the ovarian germinal epithelium, theca follicular, follicular granulosa, luteal cells, oviduct mucosal epithelial cells, and uterine glands (UG) of yaks. In conclusion, Uhrf1 was differentially expressed in the major reproductive organs during the reproductive cycle of female yaks, indicating its important regulatory role in the reproductive physiology of yaks.

We have recently discovered that the so-called subcortical maternal complex (SCMC) proteins composing of cytoplasmic lattices are destabilized in Uhrf1 knockout murine fully grown oocytes (FGOs). Here we report that human UHRF1 interacts with human NLRP5 and OOEP, which are core components of the SCMC. Moreover, NLRP5 and OOEP interact with DPPA3, which is an essential factor for exporting UHRF1 from the nucleus to the cytoplasm in oocytes. We identify that NLRP5, not OOEP, stabilizes UHRF1 protein in the cytoplasm utilizing specifically engineered cell lines mimicking UHRF1 status in oocytes and preimplantation embryos. Further, UHRF1 is destabilized both in the cytoplasm and nucleus of Nlrp5 knockout murine FGOs. Since pathogenic variants of the SCMC components frequently cause multilocus imprinting disturbance and UHRF1 is essential for maintaining CpG methylation of imprinting control regions during preimplantation development, our results suggest possible pathogenesis behind the disease, which has been a long-standing mystery., (© The Author(s) 2024. Published by Oxford University Press.)

The UHRF1 and CDC6, oncogenes play critical roles in therapeutic resistance. In the present study, we found that UHRF1 mediates androgen receptor (AR)-regulated CDC6 transcription in prostate cancer cells. In prostate cancer tissues and cell lines, levels of UHRF1 and CDC6 were simultaneously upregulated, and this was associated with worse survival. UHRF1 silencing significantly promoted the cytotoxicity and anti-prostate cancer efficacy of bicalutamide in mouse xenografts by inhibiting CDC6 gene expression. UHRF1 promoted AR-regulated CDC6 transcription by binding to the CCAAT motif near the androgen response element (ARE) in the CDC6 promoter. We further found that UHRF1 promoted androgen-dependent chromatin occupancy of AR protein by recruiting the H3K9me2/3-specific demethyltransferase KDM4C and modifying the intense heterochromatin status. Altogether, we found for the first time that UHRF1 promotes AR-regulated CDC6 transcription through a novel chromatin modification mechanism and contributes to anti-AR drug resistance in prostate cancer. Targeting AR and UHRF1 simultaneously may be a novel and promising therapeutic modality for prostate cancer. [ABSTRACT FROM AUTHOR]

Measuring protein-protein interaction (PPI) affinities is fundamental to biochemistry. Yet, conventional methods rely upon the law of mass action and cannot measure many PPIs due to a scarcity of reagents and limitations in the measurable affinity ranges. Here, we present a novel technique that leverages the fundamental concept of friction to produce a mechanical signal that correlates to binding potential. The mechanically transduced immunosorbent (METRIS) assay utilizes rolling magnetic probes to measure PPI interaction affinities. METRIS measures the translational displacement of protein-coated particles on a protein-functionalized substrate. The translational displacement scales with the effective friction induced by a PPI, thus producing a mechanical signal when a binding event occurs. The METRIS assay uses as little as 20 pmols of reagents to measure a wide range of affinities while exhibiting a high resolution and sensitivity. We use METRIS to measure several PPIs that were previously inaccessible using traditional methods, providing new insights into epigenetic recognition.

ABSTRACT HIV-1 remains incurable due to viral reservoirs, which lead to durably latent HIV infection. Identifying novel host factors and deciphering the molecular mechanisms involved in the establishment and maintenance of latency are critical to discover new targets for the development of novel anti-HIV agents. Here, we show that ubiquitin-like with PHD and RING finger domain 1 (UHRF1) modulates HIV-1 5′-long terminal repeat (LTR)-driven transcription of the viral genome as a novel HIV-1 restriction factor. Correspondingly, UHRF1 depletion reversed the latency of HIV-1 proviruses. Mechanistically, UHRF1 competed with positive transcription factor b (p-TEFb) for the binding to the cysteine-rich motifs of HIV-1 Tat via its TTD, PHD, and RING finger domains. Furthermore, UHRF1 mediated K48-linked ubiquitination and proteasomal degradation of Tat in RING-dependent ways, leading to the disruption of Tat/cyclin T1/CDK9 complex and consequential impediment of transcription elongation. In summary, our findings revealed that UHRF1 is an important mediator of HIV-1 latency by controlling Tat-mediated transcriptional activation, providing novel insights on host-pathogen interaction for modulating HIV-1 latency, beneficial for the development of anti-AIDS therapies. IMPORTANCE HIV-1 latency is systematically modulated by host factors and viral proteins. In our work, we identified a critical role of host factor ubiquitin-like with PHD and RING finger domain 1 (UHRF1) in HIV-1 latency via the modulation of the viral protein Tat stability. By disrupting the Tat/cyclin T1/CDK9 complex, UHRF1 promotes the suppression of HIV-1 transcription and maintenance of HIV-1 latency. Our findings provide novel insights in controlling Tat expression via host-pathogen interaction for modulating HIV-1 latency. Based on our results, modulating UHRF1 expression or activity by specific inhibitors is a potential therapeutic strategy for latency reversal in HIV-1 patients.

Lung cancer is listed as the most common reason for cancer-related death all over the world despite diagnostic improvements and the development of chemotherapy and targeted therapies. MicroRNAs control both physiological and pathological processes including development and cancer. A microRNA-9 to 1 (miR-9 to 1) overexpression model in lung cancer cell lines was established and miR-9 to 1 was found to significantly suppress the proliferation rate in lung cancer cell lines, colony formation in vitro, and tumorigenicity in nude mice of A549 cells. Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) was then identified to direct target of miR-9 to 1. The inhibition of UHRF1 by miR-9 to 1 causes G1 arrest and p15, p16, and p21 were re-expressed in miR-9 to 1 group in mRNA level and protein level. Silence of UHRF1 expression in A549 cells resulted in the similar re-expression of p15, p16, p21 which is similar with miR-9 to 1 infection. Therefore, we concluded that UHRF1 is a new target for miR-9 to 1 to suppress cell proliferation by re-expression of tumor suppressors p15, p16, and p21 mediated by UHRF1. [ABSTRACT FROM AUTHOR]

Downregulation of the ubiquitin-like containing PHD and ring finger 1 (UHRF1) oncogene in cancer cells in response to natural anticancer drugs, including thymoquinone (TQ), is a key event that induces apoptosis. TQ can induce UHRF1 autoubiquitination via the E3 ligase activity of its RING domain, most likely through the downregulation of herpes virus-associated ubiquitin-specific protease (HAUSP). In this study, we evaluated whether HAUSP downregulation and fast ubiquitination of UHRF1 are prerequisites for UHRF1 degradation in response to TQ in cancer cells and whether doxorubicin can mimic the effects of TQ on UHRF1 ubiquitination. RNA sequencing was performed to investigate differentially expressed genes in TQ-treated Jurkat cells. The protein expression of UHRF1, HAUSP and Bcl-2 was detected by means of Western blot analysis. The proliferation of human colon cancer (HCT-116) and Jurkat cells was analyzed via the WST-1 assay. RNA sequencing data revealed that TQ significantly decreased HAUSP expression. TQ triggered UHRF1 to undergo rapid ubiquitination as the first step in its degradation and the inhibition of its cell proliferation. TQ-induced UHRF1 ubiquitination is associated with HAUSP downregulation. Like TQ, doxorubicin induced a similar dose- and time-dependent downregulation of UHRF1 in cancer cells, but UHRF1 did not undergo ubiquitination as detected in response to TQ. Furthermore, TQ decreased Bcl-2 expression without triggering its ubiquitination. A fast UHRF1 ubiquitination is an indispensable event for its degradation in response to TQ but not for its responses to doxorubicin. TQ appears to trigger ubiquitination of UHRF1 but not of the Bcl-2 oncogene, thereby identifying UHRF1 as a specific target of TQ for cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Age-associated changes attenuate human blood system functionality through the aging of hematopoietic stem and progenitor cells (HSPCs), manifested in human populations an increase in myeloproliferative disease and even leukemia; therefore, study on HSPC senescence bears great significance to treat hematopoietic-associated disease. Furthermore, the mechanism of HSPC aging is lacking, especially the cellular memory mechanism. Here, we not only reported a new HSPC senescence model in vitro, but also propose and verify the cellular memory mechanism of HSPC aging of the Polycomb/Trithorax system. Methods: HSPCs (Lin−c-kit+ cells) were isolated and purified by magnetic cell sorting (MACS). The proportions and cell cycle distribution of cells were determined by flow cytometry; senescence-related β-galactosidase assay, transmission electron microscope (TEM), and colony-forming unit (CFU)-mix assay were detected for identification of the old HSPC model. Proteomic tests and RNA-seq were applied to analyze differential pathways and genes in the model cells. qPCR, Western blot (WB), and chromatin immunoprecipitation PCR (CHIP-PCR) were used to detect the gene expression of cell memory-related proteins. Knockdown of cell memory-related key genes was performed with shRNA interference. Results: In the model old HSPCs, β-gal activity, cell cycle, colony-forming ability, aging-related cell morphology, and metabolic pathway were significantly changed compared to the young HSPCs. Furthermore, we found the model HSPCs have more obvious aging manifestations than those of natural mice, and IL3 is the major factor contributing to HSPC aging in the model. We also observed dramatic changes in the expression level of PRC/TrxG complexes. After further exploring the downstream molecules of PRC/TrxG complexes, we found that Uhrf1 and TopII played critical roles in HSPC aging based on the HSPC senescence model. Conclusions: These findings proposed a new HSPC senescence model in vitro which we forecasted could be used to preliminary screen the drugs of the HSPC aging-related hemopathy and suggested cellular memory mechanism of HSPC aging. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5P to PtdIns(4,5)P2. They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Accordingly, a human single nucleotide polymorphism (SNP) near the PIP4K2C gene is linkedwith susceptibility to autoimmune diseases. How PIP4Ks impact on human T cell signaling is not known. Using ex vivo human primary T cells, we found that PIP4K activity is required for Treg cell signaling and immunosuppressive activity. Genetic and pharmacological inhibition of PIP4K in Tregs reduces signaling through the PI3K, mTORC1/S6, and MAPK pathways, impairs cell proliferation, and increases activation-induced cell death while sparing Tconv. PIP4K and PI3K signaling regulate the expression of the Treg master transcriptional activator FOXP3 and the epigenetic signaling protein Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). Our studies suggest that the pharmacological inhibition of PIP4K can reprogram human Treg identity while leaving Tconv cell signaling and T-helper differentiation to largely intact potentially enhancing overall immunological activity. [ABSTRACT FROM AUTHOR]

Inflammatory T cells contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Analysis of the T-cell transcriptomics data of two independent SLE patient cohorts by three machine learning models revealed the pseudogene UHRF1P as a novel SLE biomarker. The pseudogene-encoded UHRF1P protein was overexpressed in peripheral blood T cells of SLE patients. The UHRF1P protein lacks the amino-terminus of its parental UHRF1 protein, resulting in missing the proteasome-binding ubiquitin-like (Ubl) domain of UHRF1. T-cell-specific UHRF1P transgenic mice manifested the induction of IL-17A and autoimmune inflammation. Mechanistically, UHFR1P prevented UHRF1-induced Lys48-linked ubiquitination and degradation of MAP4K3 (GLK), which is a kinase known to induce IL-17A. Consistently, IL-17A induction and autoimmune phenotypes of UHRF1P transgenic mice were obliterated by MAP4K3 knockout. Collectively, UHRF1P overexpression in T cells inhibits the E3 ligase function of its parental UHRF1 and induces autoimmune diseases. • Using three machine learning statistical models, the pseudogene UHRF1P was identified as a novel biomarker for human SLE. • T-cell-specific UHRF1P transgenic mice spontaneously developed autoimmune disease. • UHFR1P prevented UHRF1-induced K48-linked ubiquitination and degradation of MAP4K3, which is a kinase known to induce IL-17A. • IL-17A induction and autoimmune phenotypes of UHRF1P transgenic mice were obliterated by MAP4K3 knockout. [ABSTRACT FROM AUTHOR]

DNA methylation is one of the most important epigenetic mark involved in many physiologic cellular processes and pathologies. During mitosis, the transmission of DNA methylation patterns from a mother to the daughter cells is ensured through the action of the Ubiquitin-like, containing PHD and RING domains, 1/DNA methyltransferase 1 (UHRF1/DNMT1) tandem. UHRF1 is involved in the silencing of many tumor suppressor genes (TSGs) via mechanisms that remain largely to be deciphered. The present study investigated the role and the regulation of UHRF1 poly-ubiquitination induced by thymoquinone, a natural anti-cancer drug, known to enhance or re-activate the expression of TSGs. We found that the auto-ubiquitination of UHRF1, induced by TQ, is mediated by reactive oxygen species, and occurs following DNA damage. We demonstrated that the poly-ubiquitinated form of UHRF1 is K63-linked and can still silence the tumor suppressor gene p16 INK4A /CDKN2A. We further showed that TQ-induced auto-ubiquitination is mediated via the activity of Tip60. Since this latter is known as a nuclear receptor co-factor, we investigated if the glucocorticoid receptor (GR) might be involved in the regulation of UHRF1 ubiquitination. Activation of the GR, with dexamethasone, did not influence auto-ubiquitination of UHRF1. However, we could observe that TQ induced a K48-linked poly-ubiquitination of GR, probably involved in the proteosomal degradation pathway. Mass-spectrometry analysis of FLAG-HA-tagged UHRF1 identified UHRF1 partners involved in DNA repair and showed that TQ increased their association with UHRF1, suggesting that poly-ubiquitination of UHRF1 is involved in the DNA repair process. We propose that poly-ubiquitination of UHRF1 serves as a scaffold to recruit the DNA repair machinery at DNA damage sites. [Display omitted] [ABSTRACT FROM AUTHOR]

The retinoblastoma (Rb) family of proteins are key regulators of cell cycle exit during development and their deregulation is associated with cancer. Rb is critical for normal retinal development and germline mutations lead to retinoblastoma making retinae an attractive system to study Rb family signaling. Rb coordinates proliferation and differentiation through the E2f family of transcription factors, a critical interaction for the role of Rb in retinal development and tumorigenesis. However, whether the roles of the different E2fs are interchangeable in controlling development and tumorigenesis in the retina or if they have selective functions remains unknown. In this study, we found that E2f family members play distinct roles in the development and tumorigenesis. In Rb;p107-deficient retinae, E2f1 and E2f3 inactivation rescued tumor formation but only E2f1 rescued the retinal development phenotype. This allowed the identification of key target genes for Rb/E2f family signaling contributing to tumorigenesis and those contributing to developmental defects. We found that Sox4 and Sox11 genes contribute to the developmental phenotype and Hells and Uhrf1 contribute to tumorigenesis. Using orthotopic human xenografts, we validated that upregulation of HELLS and UHRF1 is essential for the tumor phenotype. Also, these epigenetic regulators are important for the regulation of SYK.

Activation of transposable elements (TEs) can cause cellular damage. Cytoplasmic nucleic acid sensing pathways evolved to detect pathogens, but can also serve to cull cells with inappropriate TE activation as TEs can be viral mimetics. Epigenetic silencing of TEs is mediated in part by DNA methylation, but it is not clear if TE activation or the immune system contribute to the cellular damage caused by loss of DNA methylation. Here, we provide mechanistic insight into the observation of an activated interferon response in the liver of zebrafish larvae with deletion in critical components of the DNA methylation machinery, uhrf1 and dnmt1. We focus on dissecting the relationship between DNA methylation, TE activation and induction of an immune response through cytoplasmic DNA and double stranded RNA sensing pathways and identify tnfa as a mediator of cell death in the liver of these mutants. Integrated RNAseq and methylome analysis identified LTR transposons as the most upregulated in these mutants and also the most methylated in control larvae, indicating a direct role of DNA methylation in suppressing this TE subclass. RNAseq analysis from these same samples revealed expression signatures of a type-I interferon response and of tnfa activation, mimicking the pattern of gene expression in virally infected cells. CRISPR/Cas9 mediated depletion of the cellular antiviral sensors sting and mavs reduced expression of interferon response genes and tnfa depletion dramatically reduced cell death in uhrf1 mutant livers. This suggests that the antiviral response induced by DNA hypomethylation and TE activation in the liver is mediated by the signaling pathways activated by both cytoplasmic double stranded RNA and DNA and that tnfa mediates cell death as a potential mechanism to eliminate these damaged cells.

Maternal factors that modulate maternal-to-zygotic transition (MZT) are essential for the growth from specialized oocytes to totipotent embryos. Despite several studies, the mechanisms regulating epigenetic reprogramming during MZT remain largely elusive. UHRF1 plays a role in maintaining GC methylation in oocytes and early embryos. However, little is known about its role in mouse MZT. Here, we explored the function of maternal UHRF1 in zygotic genome regulation during early embryonic development in mice. We showed that the conditional knockout (cKO) of UHRF1 in either primordial or growing oocytes causes infertility but differentially affects early embryonic development. UHRF1 deficiency in primordial oocytes led to early embryonic developmental arrest at the two-cell stage, accompanied by significant alterations in global DNA and H3K4me3 methylation patterns. In comparison, UHRF1 ablation in growing oocytes significantly reduced developmental competence from two-cell embryos to blastocysts. At the transcriptional level, the absence of maternal UHRF1 led to aberrant transcriptional regulation of the zygotic genome during MZT at the two-cell stage. Furthermore, we observed that retrotransposable elements in UHRF1-deficient oocytes and embryos were not silenced properly; in particular, the LINE-1 and long terminal repeat (LTR) subfamily were activated abnormally. Collectively, the findings of our study reveal that maternal UHRF1 plays a critical role in establishing the correct epigenetic chromatin reprogramming of early embryos, regulating essential genes during MZT, and preserving genome integrity that drives early embryonic development in mice.

Activation of transposable elements (TEs) can cause cellular damage. Cytoplasmic nucleic acid sensing pathways evolved to detect pathogens, but can also serve to cull cells with inappropriate TE activation as TEs can be viral mimetics. Epigenetic silencing of TEs is mediated in part by DNA methylation, but it is not clear if TE activation or the immune system contribute to the cellular damage caused by loss of DNA methylation. Here, we provide mechanistic insight into the observation of an activated interferon response in the liver of zebrafish larvae with deletion in critical components of the DNA methylation machinery, uhrf1 and dnmt1. We focus on dissecting the relationship between DNA methylation, TE activation and induction of an immune response through cytoplasmic DNA and double stranded RNA sensing pathways and identify tnfa as a mediator of cell death in the liver of these mutants. Integrated RNAseq and methylome analysis identified LTR transposons as the most upregulated in these mutants and also the most methylated in control larvae, indicating a direct role of DNA methylation in suppressing this TE subclass. RNAseq analysis from these same samples revealed expression signatures of a type-I interferon response and of tnfa activation, mimicking the pattern of gene expression in virally infected cells. CRISPR/Cas9 mediated depletion of the cellular antiviral sensors sting and mavs reduced expression of interferon response genes and tnfa depletion dramatically reduced cell death in uhrf1 mutant livers. This suggests that the antiviral response induced by DNA hypomethylation and TE activation in the liver is mediated by the signaling pathways activated by both cytoplasmic double stranded RNA and DNA and that tnfa mediates cell death as a potential mechanism to eliminate these damaged cells. [ABSTRACT FROM AUTHOR]

Non-CpG DNA methylation (non-mCpG) is enriched in the genome of brain neurons and germline cells in mammals. Accumulation of non-mCpG during postnatal brain development correlates with gene regulation and inactivation of distal regulatory elements. Recently, UHRF1 has been found to contribute to de novo non-CpG methylation, however, whether UHRF1 could recognize non-mCpG is unknown. Here, we have demonstrated through calorimetric measurements that the UHRF1 SRA can recognize mCpH and fully-mCpHpG, types of non-mCpG. Our ITC binding studies endorse the preferential reading of hemi-mCpG by UHRF1 SRA and also show 6-fold weaker binding for fully-mCpG than hemi-mCpG. Despite presence of symmetrical (5-methyl cytosine) 5mCs, stoichiometry of 1:1 for UHRF1 SRA binding to fully-mCpG indicates that UHRF1 SRA may not form a stable complex with fully-mCpG DNA. Contrarily, UHRF1 SRA recognizes fully-mCpHpG with a stoichiometry of 2:1 protein to DNA duplex with binding affinity higher than fully-mCpG. Our crystal structure of UHRF1 SRA bound to fully-mCpHpG DNA reveals dual flip-out mechanism of 5mC recognition. Metadynamics studies corroborates with ITC data that UHRF1 SRA could not form a stable complex with fully-mCpG DNA. Altogether, this study demonstrates that UHRF1 SRA recognizes non-mCpG DNA and exhibits contrasting mechanisms for hemi-mCpG and fully-mCpHpG DNA recognition. • Recognition of non-CpG methylation by UHRF1 SRA is undetermined. • UHRF1 SRA can recognize both CpG and non-CpG DNA methylation. • Single base spacer is required for fully-mCpHpG recognition by UHRF1 SRA. • Binding of two molecules of UHRF1 SRA to fully-mCpG forms an unstable complex. • The study substantiates the role of UHRF1 in de novo non-CpG methylation maintenance. [ABSTRACT FROM AUTHOR]

Background: Transcription factor B cell lymphoma 6 (BCL6) is a master regulator of T follicular helper (Tfh) cells, which play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanisms by which BCL6 expression is regulated are poorly understood. Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an important epigenetic factor that regulates DNA methylation and histone modifications. In the present study, we assessed whether UHRF1 can regulate BCL6 expression and influence the differentiation and proliferation of Tfh cells. Results: Compared to healthy controls, the mean fluorescence intensity of UHRF1 (UHRF1-MFI) in Tfh cells from SLE patients was significantly downregulated, whereas that of BCL6 (BCL6-MFI) was significantly upregulated. In vitro, UHRF1 knockdown led to BCL6 overexpression and promoted Tfh cell differentiation. In contrast, UHRF1 overexpression led to BCL6 downregulation and decreased Tfh cell differentiation. In vivo, conditional UHRF1 gene knockout (UHRF1-cKO) in mouse T cells revealed that UHRF1 depletion can enhance the proportion of Tfh cells and induce an augmented GC reaction in mice treated with NP-keyhole limpet hemocyanin (NP-KLH). Mechanistically, UHRF1 downregulation can decrease DNA methylation and H3K27 trimethylation (H3K27me3) levels in the BCL6 promoter region of Tfh cells. Conclusions: Our results demonstrated that UHRF1 downregulation leads to increased BCL6 expression by decreasing DNA methylation and H3K27me3 levels, promoting Tfh cell differentiation in vitro and in vivo. This finding reveals the role of UHRF1 in regulating Tfh cell differentiation and provides a potential target for SLE therapy. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to explore the value of UHRF1 in the early diagnosis and prognosis of bladder cancer. Methods: In this paper, we collected the paracancerous and cancerous tissues of 26 patients with bladder cancer. At the same time, human BCa cells and T24 cells were used as in vitro models. CCK-8 analysis, TUNEL staining, LDH activity and the level of Caspase 3/8/9 protein surface activity were used to detect the effect of UHRF1. qRT-PCR detection, gene chip and Western blotting were used to detect the downstream pathway of UHRF1. Results: Compared with adjacent tissues, UHRF1 expression was significantly activated in bladder urothelial carcinoma membrane tissue. At the same time, the expression of UHRF1 in the bladder urothelial carcinoma membrane group of III-IV bladder cancer patients was significantly higher than that of the I-II bladder cancer patient group. Up-regulation of UHRF1 can promote the proliferation of bladder cancer cells and reduce the level of LDH activity. When UHRF1 was up-regulated for 3 and 5 days, Caspase-3/9 activity in bladder cancer cells was inhibited. UHRF1 overexpression can activate VEGF and HIF1αm RNA and protein expression. Activating the HIF1α-VEGF pathway inhibits the regulation of UHRF1 on the proliferation of bladder cancer cells. Conclusion: UHRF1 promotes the proliferation of bladder cancer cells through the HIF1α-VEGF pathway, suggesting that UHRF1 can be used as a molecular marker for predicting bladder cancer. [ABSTRACT FROM AUTHOR]

Background: It was reported that circular RNAs (circRNAs) exerted important functions in various human cancers. However, the function of circFAT1 was less known. The purpose of this study was to reveal the functional mechanism of circFAT1 in colorectal cancer (CRC). Materials and Methods: Quantitative real-time polymerase chain reaction and Western blot assay were used to detect the levels of genes. Cell proliferation ability was assessed by 3-(4, 5-dimethyl-2-thiazoyl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry was used to investigate cell apoptosis rate. The glucose consumption and lactate production were determined using related kits. Furthermore, the interaction between circFAT1 or ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) and miR-520b or miR-302c-3p was predicted by starbase3.0, and then confirmed by the dual-luciferase reporter assay. Besides, xenograft experiment was performed to analyze the effect of circFAT1 on tumor growth in vivo. Results: The levels of circFAT1 and UHRF1 were increased, as well as the levels of miR-520b and miR-302c-3p were decreased in CRC tissues and cells. CircFAT1 knockdown suppressed cell proliferation, cycle, and glycolysis as well as induced apoptosis. Interestingly, circFAT1 was a sponge of miR-520b and miR-302c-3p, and miR-520b and miR-302c-3p could target UHRF1. Both miR-520b overexpression and miR-302c-3p overexpression inhibited CRC cell growth. Furthermore, both miR-520b knockdown and miR-302c-3p depletion weakened the effect of circFAT1 knockdown on the growth of CRC cells. Besides, circFAT1 depletion repressed tumor growth in vivo. Conclusion: The authors' findings suggested that circFAT1 upregulated UHRF1 to affect CRC cell proliferation, apoptosis, and glycolysis through targeting miR-520b and miR-302c-3p, providing theoretical basis for the treatment of CRC. [ABSTRACT FROM AUTHOR]

Purpose : Chronic myeloid leukemia stem cells (CML-LSCs) are posited as the primary instigators of resistance to tyrosine kinase inhibitors (TKIs) and recurrence of CML. Ubiquitination, a post-translational modification, has been implicated in the worsening process of CML. A more detailed understanding of their crosstalk needs further investigation. Our research aims to explore the potential ubiquitination-related genes in CML-LSC using bioinformatics analysis that might be the target for the eradication of LSCs. Methods : The ubiquitination modification-related differentially expressed genes (UUC-DEGs) between normal hematopoietic stem cells (HSCs) and LSCs were obtained from GSE47927 and iUUCD database. Subsequently, the hub UUC-DEGs were identified through protein-protein interaction (PPI) network analysis utilizing the STRING database and the MCODE plug-in within the Cytoscape platform. The upstream regulation network of the hub UUC-DEGs was studied by hTFtarget, PROMO, miRDB and miRWalk databases respectively. Then the correlation between the hub UUC-DEGs and the immune cells was analyzed by the CIBERSORT algorithm and "ggcorrplot" package. Finally, we validated the function of hub UUC-DEGs in CML animal models, CML cell lines and CD34 + cells of the GSE24739 dataset. Results : There is a strong association between the 4 hub UUC genes ( AURKA, Fancd2, Cdc20 and Uhrf1 ) of LSCs and the infiltration of CD4 + /CD8 + T cells, NK cells and monocytes. 8 TFs and 23 miRNAs potentially targeted these 4 hub genes were constructed. Among these hub genes, Fancd2, Cdc20 and Uhrf1 were found to be highly expressed in CML-LSC, which knocking down resulted in significant inhibition of CML cell proliferation. Conclusions : From the perspective of bioinformatics analysis, UHRF1 and CDC20 were identified as the novel key ubiquitination-related genes in CML-LSCs and the pathogenesis of CML., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Summary: UHRF1 is a key regulator in DNA methylation maintenance. It binds histone H3K9me2/3 and hemi-methylated DNA and recruits DNMT1 to DNA replication forks during S phase. However, the regulatory mechanism of hemi-methylated DNA binding activity of UHRF1 remains unknown. In this study, we reveal that acetylation of UHRF1 is regulated by PCAF and HDAC1. We show that UHRF1 acetylation at K490 attenuates its binding affinity to hemi-methylated DNA. We analyze genome-wide DNA methylation and gene-expression patterns using stable cell lines and discover that cells where the endogenous UHRF1 is replaced with an acetyl-mimetic (UHRF1 K490Q) mutant show deficiencies in inherited DNA methylation and show different gene-expression patterns in genes related to cell survival. These results reveal that precise regulation of UHRF1 acetylation is required to maintain DNA methylation during cell division and control cell survival.

Abstract Background Deer antlers are bony structures that re-grow at very high rates, making them an attractive model for studying rapid bone regeneration. Methods To identify the genes that are involved in this fast pace of bone growth, an in vitro RNA-seq model that paralleled the sharp differences in bone growth between deer antlers and humans was established. Subsequently, RNA-seq (> 60 million reads per library) was used to compare transcriptomic profiles. Uniquely expressed deer antler proliferation as well as mineralization genes were identified via a combination of differential gene expression and subtraction analysis. Thereafter, the physiological relevance as well as contributions of these identified genes were determined by immunofluorescence, gene overexpression, and gene knockdown studies. Results Cell characterization studies showed that in vitro-cultured deer antler-derived reserve mesenchyme (RM) cells exhibited high osteogenic capabilities and cell surface markers similar to in vivo counterparts. Under identical culture conditions, deer antler RM cells proliferated faster (8.6–11.7-fold increase in cell numbers) and exhibited increased osteogenic differentiation (17.4-fold increase in calcium mineralization) compared to human mesenchymal stem cells (hMSCs), paralleling in vivo conditions. Comparative RNA-seq identified 40 and 91 previously unknown and uniquely expressed fallow deer (FD) proliferation and mineralization genes, respectively, including uhrf1 and s100a10. Immunofluorescence studies showed that uhrf1 and s100a10 were expressed in regenerating deer antlers while gene overexpression and gene knockdown studies demonstrated the proliferation contributions of uhrf1 and mineralization capabilities of s100a10. Conclusion Using a simple, in vitro comparative RNA-seq approach, novel genes pertinent to fast bony antler regeneration were identified and their proliferative/osteogenic function was verified via gene overexpression, knockdown, and immunostaining. This combinatorial approach may be applicable to discover unique gene contributions between any two organisms for a given phenomenon-of-interest.

Abstract Background Hepatoblastoma (HB) is the most common liver tumor of childhood and occurs predominantly within the first 3 years of life. In accordance to its early manifestation, HB has been described to display an extremely low mutation rate. As substitute, epigenetic modifiers seem to play an exceptional role in its tumorigenesis, which holds promise to develop targeted therapies and establish biomarkers for patient risk stratification. Results We examined the role of a newly described protein complex consisting of three epigenetic regulators, namely E3 ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), ubiquitin-specific-processing protease 7 (USP7), and DNA methyltransferase 1 (DNMT1), in HB. We found the complex to be located on the promoter regions of the pivotal HB-associated tumor suppressor genes (TSGs) HHIP, IGFBP3, and SFRP1 in HB cells, thereby leading to strong repression through DNA methylation and histone modifications. Consequently, knockdown of UHRF1 led to DNA demethylation and loss of the repressive H3K9me2 histone mark at the TSG loci with their subsequent transcriptional reactivation. The observed growth impairment of HB cells upon UHRF1 knockdown could be attributed to reduced expression of genes involved in cell cycle progression, negative regulation of cell death, LIN28B signaling, and the adverse 16-gene signature, as revealed by global RNA sequencing. Clinically, overexpression of UHRF1 in primary tumor tissues was significantly associated with poor survival and the prognostic high-risk 16-gene signature. Conclusion These findings suggest that UHRF1 is critical for aberrant TSG silencing and sustained growth signaling in HB and that UHRF1 overexpression levels might serve as a prognostic biomarker and potential molecular target for HB patients.

Kirsten rat sarcoma virus oncogene homolog (KRAS) mutant lung cancer remains a challenge to cure and chemotherapy is the current standard treatment in the clinic. Hence, understanding molecular mechanisms underlying the sensitivity of KRAS mutant lung cancer to chemotherapy could help uncover unique strategies to treat this disease. Here we report a compound library screen and identification of cardiac glycosides as agents that selectively enhance the in vitro and in vivo effects of chemotherapy on KRAS mutant lung cancer. Quantitative mass spectrometry reveals that cardiac glycosides inhibit DNA double strand break (DSB) repair through suppressing the expression of UHRF1, an important DSB repair factor. Inhibition of UHRF1 by cardiac glycosides was mediated by specific suppression of the oncogenic KRAS pathway. Overexpression of UHRF1 rescued DSB repair inhibited by cardiac glycosides and depletion of UHRF1 mitigated cardiac glycoside-enhanced chemotherapeutic drug sensitivity in KRAS mutant lung cancer cells. Our study reveals a targetable dependency on UHRF1-stimulated DSB repair in KRAS mutant lung cancer in response to chemotherapy. [ABSTRACT FROM AUTHOR]

Cancer therapeutics produce reactive oxygen species (ROS) that damage the cancer genome and lead to cell death. However, cancer cells can resist ROS-induced cytotoxicity and survive. We show that nuclear-localized uracil-DNA N-glycosylase isoform 2 (UNG2) has a critical role in preventing ROS-induced DNA damage and enabling cancer-cell resistance. Under physiological conditions, UNG2 is targeted for rapid degradation via an interaction with the E3 ligase UHRF1. In response to ROS, however, UNG2 protein in cancer cells exhibits a remarkably extended half-life. Upon ROS exposure, UNG2 is deacetylated at lysine 78 by histone deacetylases, which prevents the UNG2–UHRF1 interaction. Accumulated UNG2 protein can thus excise the base damaged by ROS and enable the cell to survive these otherwise toxic conditions. Consequently, combining HDAC inhibitors (to permit UNG2 degradation) with genotoxic agents (to produce cytotoxic cellular levels of ROS) leads to a robust synergistic killing effect in cancer cells in vitro. Altogether, these data support the application of a novel approach to cancer treatment based on promoting UNG2 degradation by altering its acetylation status using an HDAC inhibitor. Image 1 • UNG2 confers cell resistance to H 2 O 2 , which can be targeted for cancer treatment. • UNG2 is deacetylated and stabilized in response to H 2 O 2 treatment. • E3 ligase UHRF1 interacts with and ubiquitinates acetylated UNG2 for proteasomal degradation. • Acetylation at K78 of UNG2 promotes UNG2-UHRF1 interaction and UNG2 degradation. • HDACi promotes acetylated-UNG2 degradation and enhances cancer toxicity of ROS reagents. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a common chronic degenerative joint disease, and chondrocyte apoptosis is one of most important pathological changes of OA pathogenesis. Growing studies have shown that Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an important epigenetic regulatory factor that regulates cell proliferation and apoptosis of various tumors, but its role in OA remains ill-defined. In the present study, we found that UHRF1 expression was increased in human OA cartilage tissues, compared with normal cartilage tissues. Interleukin-1β (IL-1β), a major inflammatory cytokine that promotes cartilage degradation in OA, was used to stimulate primary human chondrocytes in vitro. The expression of UHRF1 was also enhanced in IL-1β-induced chondrocytes. Moreover, down-regulation of UHRF1 induced an increase on cell proliferation and autophagy, and a decrease on apoptosis of chondrocytes after IL-1β treatment. Further data indicated that silencing UHRF1 attenuated the up-regulation of IL-1β on phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway in chondrocytes. Then, an activator of PI3K weakened the effect of UHRF1 silencing on cell proliferation, autophagy, apoptosis of IL-1β-induced chondrocytes, and the cell autophagy special inhibitor 3-methyladenine (3-MA) also showed a same impact on UHRF1, hence suggesting that knockdown of UHRF1 enhances cell autophagy to protect chondrocytes from apoptosis in OA through PI3K/AKT/mTOR signaling pathway. In conclusion, our study suggests that UHRF1 may be a potential regulator of chondrocyte apoptosis in the pathogenesis of OA. • UHRF1 was highly expressed in OA cartilage tissues and IL-1β-induced chondrocytes. • Silencing UHRF1 suppressed apoptosis and enhanced autophagy in IL-1β-induced chondrocytes. • Silencing UHRF1 down-regulated IL-1β-activated PI3K/AKT/mTOR signaling pathway in chondrocytes. • Silencing UHRF1 promoted autophagy to prevent chondrocytes apoptosis through PI3K/AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of ubiquitin-like with PHD and ring finger domains 1 (UHRF1) on the radiosensitivity of esophageal squamous carcinoma cells and explore its mechanism. Methods The shRNA sequence was designed with human UHRF1 as the target, and the UHRF1-shRNA was transfected into Eca-109 cells mediated by lentivirus. The expressions of UHRF1 mRNA and protein before and after transfection were determined by fluorescence quantitative PCR and Western blotting. The radiosensitivity of Eca-109 cells after down-regulation of UHRF1 gene was assessed by colony formation assay. The effect of silencing UHRF1 on the apoptosis of Eca-109 cells before and after X-ray irradiation was detected by flow cytometry. Western blotting was used to detect the effects of UHRF1 silencing and X-ray irradiation on the expressions of apoptosis-related proteins Bcl-2, caspase-3 and proteins related to AKT/mTOR signaling pathway in Eca-109 cells. Results We successfully constructed an Eca-109 shUHRF1 cell line with UHRF1 stablely down-regulated. Colony formation assays showed that the radiosensitivity of Eca-109 cells was increased after down-regulation of UHRF1 expression compared with the NC group. The proportion of apoptotic cells in Eca-109 cells was increased, while this change was more obvious after irradiation. Compared with NC group, down-regulation of UHRF1 expression increased the level of active caspase-3 protein and decreased the level of the apoptosis inhibitory protein Bcl-2; the expression levels of p-AKT and p-mTOR protein were decreased. The changes in these four proteins in Eca-109 cells with down-regulation of UHRF1 combined with 6Gy X-ray irradiation were more obvious compared with the NC group. Conclusion UHRF1 knock-down increased the radiosensitivity of ESCC via inhibiting the Akt/mTOR signaling pathway activity and inducing the apoptosis of the cells. [ABSTRACT FROM AUTHOR]

Persistent infection with high-risk strains of human papillomavirus (HPV) is the primary cause of cervical cancer, the fourth most common cancer among women worldwide. Two oncoproteins encoded by the HPV genome, E6 and E7, are required for epigenetic modifications that promote cervical cancer development. We found that knockdown of HPV E6/E7 by siRNA reduced the levels of ubiquitin-like containing PHD and RING finger domain 1 (UHRF1) but increased the levels of gelsolin (GSN) in early stage cervical cancer cells. In addition, we found that UHRF1 levels were increased and GSN levels were decreased in early stage cervical cancer compared with those in normal cervical tissues, as shown by Western blot analysis, immunohistochemistry, and analysis of the Oncomine database. Moreover, knockdown of UHRF1 resulted in increased cell death in cervical cancer cell lines. Treatment of E6/E7-transformed HaCaT (HEK001) cells and HeLa cells with the DNA-hypomethylating agent 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor Trichostatin A increased GSN expression levels. UHRF1 knockdown in HEK001 cells by siRNA or the UHRF1 antagonist thymoquinone increased GSN levels, induced cell cycle arrest and apoptosis, and increased the levels of p27 and cleaved PARP. Those results indicate that upregulation of UHRF1 by HPV E6/E7 causes GSN silencing and a reduction of cell death in early stage cervical cancer, suggesting that GSN might be a useful therapeutic target in early stage cervical cancer. • UHRF1 levels are increased whereas gelsolin levels are decreased in early stage cervical cancer. • HPV E6/E7 increases UHRF1 levels and decreases gelsolin levels in early stage cervical cancer. • UHRF1 knockdown increases gelsolin levels and cell death in early stage cervical cancer. • UHRF1 silences gelsolin, promoting cervical cancer development. [ABSTRACT FROM AUTHOR]