Systematic analysis of DNA methylation-mediated TF dysregulation on lncRNAs reveals critical roles in tumor immunity
Ontology highlight
ABSTRACT:
SUBMITTER: Yin J
PROVIDER: S-EPMC10630662 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundPreeclampsia (PE) is a heterogeneous, hypertensive disorder of pregnancy, with no robust biomarkers or effective treatments. PE increases the risk of poor outcomes for both the mother and the baby. Methylation-mediated transcriptional dysregulation motifs (methTDMs) could contribute the PE development. However, precise functional roles of methTDMs in PE have not been globally described.MethodsHere, we develop a comprehensive and computational pipeline to identify PE-specific methTDMs following TF, gene, methylation expression profile, and experimentally verified TF-gene interactions.ResultsThe regulation patterns of methTDMs are multiple and complex in PE and contain relax inhibition, intensify inhibition, relax activation, intensify activation, reverse activation, and reverse inhibition. A core module is extracted from global methTDM network to further depict the mechanism of methTDMs in PE. The common and specific features of any two kinds of regulation pattern are also analyzed in PE. Some key methylation sites, TFs, and genes such as IL2RG are identified in PE. Functional analysis shows that methTDMs are associated with immune-, insulin-, and NK cell-related functions. Drug-related network identifies some key drug repurposing candidates such as NADH.ConclusionCollectively, the study highlighted the effect of methylation on the transcription process in PE. MethTDMs could contribute to identify specific biomarkers and drug repurposing candidates for PE.
| S-EPMC6993410 | biostudies-literature
Project description:Ovarian cancer is a significant cause of cancer-related mortality in women. Over the past 3 decades, there has been a high incidence of recurrent chemoresistant disease, despite the relative effectiveness of current treatment strategies. This is partly attributed to cancer stem cells (CSC), a subpopulation that has acquired stem cell properties that allow these cells to evade standard chemotherapy and cause disease recurrence. Therefore, there is an urgent need for basic knowledge about CSC to develop innovative therapeutic approaches for ovarian cancer. These CSC subpopulations have been identified in ovarian cancer cell lines, tumors or ascites, and findings suggest that ovarian CSCs may be as heterogeneous as the disease itself. CSCs regulate the phenotype and function of immune cells involved in antitumor immunity, so a better understanding of the signaling pathways that interact between CSCs, immune cells and tumor cells will pave the way for the clinical application of CS in cancer immunotherapy. This review will focus on the markers currently used to identify and isolate these cells summarize current knowledge on the molecular and cellular mechanisms responsible for CSC-dependent regulation of antitumor immune responses. We will discuss the signaling pathways involved in CSC survival, replication, and differentiation as well as potential therapeutic targeting strategies.
| S-EPMC9685611 | biostudies-literature
Project description:Activation of the cGAS/STING innate immunity pathway is essential and effective for anti-tumor immunotherapy. However, it remains largely elusive how tumor-intrinsic cGAS signaling is suppressed to facilitate tumorigenesis by escaping immune surveillance. Here, we report that the protein arginine methyltransferase, PRMT1, methylates cGAS at the conserved Arg133 residue, which prevents cGAS dimerization and suppresses the cGAS/STING signaling in cancer cells. Notably, genetic or pharmaceutical ablation of PRMT1 leads to activation of cGAS/STING-dependent DNA sensing signaling, and robustly elevates the transcription of type I and II interferon response genes. As such, PRMT1 inhibition elevates tumor-infiltrating lymphocytes in a cGAS-dependent manner, and promotes tumoral PD-L1 expression. Thus, combination therapy of PRMT1 inhibitor with anti-PD-1 antibody augments the anti-tumor therapeutic efficacy in vivo. Our study therefore defines the PRMT1/cGAS/PD-L1 regulatory axis as a critical factor in determining immune surveillance efficacy, which serves as a promising therapeutic target for boosting tumor immunity.
| S-EPMC10188589 | biostudies-literature
Project description:During embryo development, DNA methylation is established by DNMT3A/3B and subsequently maintained by DNMT1. While much research has been done in this field, the functional significance of DNA methylation in embryogenesis remains unknown. Here, we establish a system of simultaneous inactivation of multiple endogenous genes in zygotes through screening for base editors that can efficiently introduce a stop codon. Embryos with mutations in Dnmts and/or Tets can be generated in one step with IMGZ. Dnmt-null embryos display gastrulation failure at E7.5. Interestingly, although DNA methylation is absent, gastrulation-related pathways are down-regulated in Dnmt-null embryos. Moreover, DNMT1, DNMT3A, and DNMT3B are critical for gastrulation, and their functions are independent of TET proteins. Hypermethylation can be sustained by either DNMT1 or DNMT3A/3B at some promoters, which are related to the suppression of miRNAs. The introduction of a single mutant allele of six miRNAs and paternal IG-DMR partially restores primitive streak elongation in Dnmt-null embryos. Thus, our results unveil an epigenetic correlation between promoter methylation and suppression of miRNA expression for gastrulation and demonstrate that IMGZ can accelerate deciphering the functions of multiple genes in vivo.
| S-EPMC10203112 | biostudies-literature
Project description:Activation of tumor-intrinsic innate immunity has been a major strategy for improving immunotherapy. Previously, we reported an autophagy-promoting function of the deubiquitinating enzyme TRABID. Here, we identify a critical role of TRABID in suppressing anti-tumor immunity. Mechanistically, TRABID is upregulated in mitosis and governs mitotic cell division by removing K29-linked polyubiquitin chain from Aurora B and Survivin, thereby stabilizing the entire chromosomal passenger complex. TRABID inhibition causes micronuclei through a combinatory defect in mitosis and autophagy and protects cGAS from autophagic degradation, thereby activating the cGAS/STING innate immunity pathway. Genetic or pharmacological inhibition of TRABID promotes anti-tumor immune surveillance and sensitizes tumors to anti-PD-1 therapy in preclinical cancer models in male mice. Clinically, TRABID expression in most solid cancer types correlates inversely with an interferon signature and infiltration of anti-tumor immune cells. Our study identifies a suppressive role of tumor-intrinsic TRABID in anti-tumor immunity and highlights TRABID as a promising target for sensitizing solid tumors to immunotherapy.
| S-EPMC10220035 | biostudies-literature
Project description:Accumulation of ?-catenin in the nucleus is a hallmark of activation of the Wnt/?-catenin signaling pathway, which drives development of a large proportion of human cancers. However, the mechanism of ?-catenin nuclear translocation has not been well investigated. Here we report biological significance of SMYD2-mediated lysine 133 (K133) methylation of ?-catenin on its nuclear translocation. Knockdown of SMYD2 attenuates the nuclear localization of ?-catenin protein in human cancer cells. Consequently, transcriptional levels of well-known Wnt-signaling molecules, cMYC and CCND1, are significantly reduced. Substitution of lysine 133 to alanine in ?-catenin almost completely abolishes its nuclear localization. We also demonstrate the K133 methylation is critical for the interaction of ?-catenin with FOXM1. Furthermore, after treatment with a SMYD2 inhibitor, significant reduction of nuclear ?-catenin and subsequent induction of cancer cell death are observed. Accordingly, our results imply that ?-catenin methylation by SMYD2 promotes its nuclear translocation and activation of Wnt signaling.
| S-EPMC5593527 | biostudies-literature
Project description:RNA editing is a crucial post-transcriptional process that influences gene expression and increases the diversity of the proteome as a result of amino acid substitution. Recently, the APOBEC3 family has emerged as a significant player in this mechanism, with APOBEC3A (A3A) having prominent roles in base editing during immune and stress responses. APOBEC3B (A3B), another family member, has gained attention for its potential role in generating genomic DNA mutations in breast cancer. In this study, we coupled an inducible expression cell model with a novel methodology for identifying differential variants in RNA (DVRs) to map A3B-mediated RNA editing sites in a breast cancer cell model. Our findings indicate that A3B engages in selective RNA editing including targeting NEAT1 and MALAT1 long non-coding RNAs that are often highly expressed in tumour cells. Notably, the binding of these RNAs sequesters A3B and suppresses global A3B activity against RNA and DNA. Release of A3B from NEAT1/MALAT1 resulted in increased A3B activity at the expense of A3A activity suggesting a regulatory feedback loop between the two family members. This research substantially advances our understanding of A3B's role in RNA editing, its mechanistic underpinnings, and its potential relevance in the pathogenesis of breast cancer.
| S-EPMC11554567 | biostudies-literature
Project description:LIGHT (TNFSF14) is a member of the TNF superfamily involved in inflammation and defence against infection. LIGHT signals via two cell-bound receptors; herpes virus entry mediator (HVEM) and lymphotoxin-beta receptor (LT?R). We found that LIGHT is critical for control of hepatic parasite growth in mice with visceral leishmaniasis (VL) caused by infection with the protozoan parasite Leishmania donovani. LIGHT-HVEM signalling is essential for early dendritic cell IL-12/IL-23p40 production, and the generation of IFN?- and TNF-producing T cells that control hepatic infection. However, we also discovered that LIGHT-LT?R interactions suppress anti-parasitic immunity in the liver in the first 7 days of infection by mechanisms that restrict both CD4(+) T cell function and TNF-dependent microbicidal mechanisms. Thus, we have identified distinct roles for LIGHT in infection, and show that manipulation of interactions between LIGHT and its receptors may be used for therapeutic advantage.
| S-EPMC3188526 | biostudies-literature
Project description:As one of the most common malignancies worldwide, gastric cancer contributes to cancer death with a high mortality rate partly responsible for its out-of-control progression as well as limited diagnosis. DNA methylation, one of the epigenetic events, plays an essential role in the carcinogenesis of many cancers, including gastric cancer. Long non-coding RNAs have emerged as the significant factors in the cancer progression functioned as the oncogene genes, the suppressor genes and regulators of signaling pathways over the decade. Intriguingly, increasing reports, recently, have claimed that abnormal DNA methylation regulates the expression of lncRNAs as tumor suppressor genes in gastric cancer and lncRNAs as regulators could exert the critical influence on tumor progression through acting on DNA methylation of other cancer-related genes. In this review, we summarized the DNA methylation-associated lncRNAs in gastric cancer which play a large impact on tumor progression, such as proliferation, invasion, metastasis and so on. Furthermore, the underlying molecular mechanism and signaling pathway might be developed as key points of gastric cancer range from diagnosis to prognosis and treatment in the future.
| S-EPMC9270757 | biostudies-literature
Project description:It is well understood that antigen-presenting cells (APCs) within tumors typically do not maintain cytotoxic T cell (CTL) function, despite engaging them. Across multiple mouse tumor models and human tumor biopsies, we have delineated the intratumoral dendritic cell (DC) populations as distinct from macrophage populations. Within these, CD103(+) DCs are extremely sparse and yet remarkably capable CTL stimulators. These are uniquely dependent on IRF8, Zbtb46, and Batf3 transcription factors and are generated by GM-CSF and FLT3L cytokines. Regressing tumors have higher proportions of these cells, T-cell-dependent immune clearance relies on them, and abundance of their transcripts in human tumors correlates with clinical outcome. This cell type presents opportunities for prognostic and therapeutic approaches across multiple cancer types.
| S-EPMC4254577 | biostudies-literature