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Biomarker Research Feb 2024Small noncoding RNAs play an important role in various disease states, including cancer. PIWI proteins, a subfamily of Argonaute proteins, and PIWI-interacting RNAs... (Review)
Review
Small noncoding RNAs play an important role in various disease states, including cancer. PIWI proteins, a subfamily of Argonaute proteins, and PIWI-interacting RNAs (piRNAs) were originally described as germline-specific molecules that inhibit the deleterious activity of transposable elements. However, several studies have suggested a role for the piRNA-PIWI axis in somatic cells, including somatic stem cells. Dysregulated expression of piRNAs and PIWI proteins in human tumors implies that, analogously to their roles in undifferentiated cells under physiological conditions, these molecules may be important for cancer stem cells and thus contribute to cancer progression. We provide an overview of piRNA biogenesis and critically review the evidence for the role of piRNA-PIWI axis in cancer stem cells. In addition, we examine the potential of piRNAs and PIWI proteins to become biomarkers in cancer.
PubMed: 38303021
DOI: 10.1186/s40364-024-00563-3 -
BMC Genomics Feb 2024Circadian rhythm is crucial to the function of the immune system. Disorders of the circadian rhythm can contribute to inflammatory diseases such as Ulcerative colitis...
BACKGROUND
Circadian rhythm is crucial to the function of the immune system. Disorders of the circadian rhythm can contribute to inflammatory diseases such as Ulcerative colitis (UC). This Mendelian Randomization (MR) analysis applies genetic tools to represent the aggregated statistical results of exposure to circadian rhythm disorders and UC and its comorbidities, allowing for causal inferences.
METHODS
Summary statistics of protein, DNA methylation and gene expression quantitative trait loci in individuals of European ancestry (pQTL, mQTL, and eQTL, respectively) were used. Genetic variants located within or near 152 circadian clock-related genes and closely related to circadian rhythm disorders were selected as instrumental variables. Causal relationships with UC and its comorbidities were then estimated through employed Summary data-based Mendelian Randomization (SMR) and Inverse-Variance-Weighted MR (IVW-MR).
RESULTS
Through preliminary SMR analysis, we identified a potential causal relationship between circadian clock-related genes and UC along with its comorbidities, which was further confirmed by IVW-MR analysis. Our study identified strong evidence of positive correlation involving seven overlapping genes (CSNK1E, OPRL1, PIWIL2, RORC, MAX, PPP5C, and AANAT) through MWAS and TWAS in UC, four overlapping genes (OPRL1, CHRNB2, FBXL17, and SIRT1) in UC with PSC, and three overlapping genes (ARNTL, USP7, and KRAS) in UC with arthropathy.
CONCLUSIONS
This SMR study demonstrates the causal effect of circadian rhythm disorders in UC and its comorbidities. Furthermore, our investigation pinpointed candidate genes that could potentially serve as drug targets.
Topics: Humans; Colitis, Ulcerative; Circadian Clocks; Mendelian Randomization Analysis; Comorbidity; Chronobiology Disorders; Genome-Wide Association Study; Ubiquitin-Specific Peptidase 7; Argonaute Proteins
PubMed: 38302916
DOI: 10.1186/s12864-024-10003-z -
Nature Communications Feb 2024RNA interference (RNAi) is a conserved gene silencing process that exists in diverse organisms to protect genome integrity and regulate gene expression. In C. elegans,...
RNA interference (RNAi) is a conserved gene silencing process that exists in diverse organisms to protect genome integrity and regulate gene expression. In C. elegans, the majority of RNAi pathway proteins localize to perinuclear, phase-separated germ granules, which are comprised of sub-domains referred to as P granules, Mutator foci, Z granules, and SIMR foci. However, the protein components and function of the newly discovered SIMR foci are unknown. Here we demonstrate that HRDE-2 localizes to SIMR foci and interacts with the germline nuclear Argonaute HRDE-1 in its small RNA unbound state. In the absence of HRDE-2, HRDE-1 exclusively loads CSR-class 22G-RNAs rather than WAGO-class 22G-RNAs, resulting in inappropriate H3K9me3 deposition on CSR-target genes. Thus, our study demonstrates that the recruitment of unloaded HRDE-1 to germ granules, mediated by HRDE-2, is critical to ensure that the correct small RNAs are used to guide nuclear RNA silencing in the C. elegans germline.
Topics: Animals; Argonaute Proteins; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Germ Cells; RNA Interference; RNA, Small Interfering
PubMed: 38302462
DOI: 10.1038/s41467-024-45245-8 -
Vavilovskii Zhurnal Genetiki I Selektsii Dec 2023RNA interference is a gene silencing mechanism that plays an important role in genetic regulation in a number of eukaryotes. Argonaute (AGO) proteins are central to the...
The effect of salicylic and jasmonic acids on the activity of SnAGO genes in the fungus Stagonospora nodorum Berk. in in vitro culture and during infection of wheat plants.
RNA interference is a gene silencing mechanism that plays an important role in genetic regulation in a number of eukaryotes. Argonaute (AGO) proteins are central to the complex RNA interference system. However, their role in this mechanism, both in the host plant organism and in the pathogen, has not yet been fully elucidated. In this work, we identified and phylogenetically analyzed the SnAGO1, SnAGO2, SnAGO3, and SnAGO18 genes of the pathogenic fungus Stagonospora nodorum Berk., and analyzed their expression under conditions of infection of plants with varying degrees of resistance to the pathogen. The expression level against the background of plant immunization with the resistance inducers salicylic and jasmonic acids was assessed. In addition, the activity of these genes in the culture of the fungus in vitro was studied under the direct influence of resistance inducers on the mycelium of the fungus. Earlier activation of the SnAGO genes in in vitro culture under the influence of salicylic and jasmonic acids suggests their sensitivity to it. In an in vivo system, plant immunization to induce the accumulation of pathogen SnAGO transcripts was found. At the same time, the SnAGO genes of the fungus S. nodorum, when interacting with plant cells, reacted depending on the degree of host resistance: the highest level of transcripts in the resistant variety was observed. Thus, our data prove that the SnAGO genes of the fungus S. nodorum effectively interact with the host defense system in direct proportion to the degree of resistance of the latter to the pathogen. It was proposed to use the ratio of the transcriptional activity of the fungal reference gene SnTub to the host TaRLI gene as a marker of disease development in the initial period of the infectious process.
PubMed: 38239968
DOI: 10.18699/VJGB-23-115 -
G3 (Bethesda, Md.) Mar 2024Gene regulation in changing environments is critical for maintaining homeostasis. Some animals undergo a stress-resistant diapause stage to withstand harsh environmental...
Gene regulation in changing environments is critical for maintaining homeostasis. Some animals undergo a stress-resistant diapause stage to withstand harsh environmental conditions encountered during development. MicroRNAs are one mechanism for regulating gene expression during and after diapause. MicroRNAs downregulate target genes posttranscriptionally through the activity of the microRNA-induced silencing complex. Argonaute is the core microRNA-induced silencing complex protein that binds to both the microRNA and to other microRNA-induced silencing complex proteins. The 2 major microRNA Argonautes in the Caenorhabditis elegans soma are ALG-1 and ALG-2, which function partially redundantly. Loss of alg-1 [alg-1(0)] causes penetrant developmental phenotypes including vulval defects and the reiteration of larval cell programs in hypodermal cells. However, these phenotypes are essentially absent if alg-1(0) animals undergo a diapause stage called dauer. Levels of the relevant microRNAs are not higher during or after dauer, suggesting that activity of the microRNA-induced silencing complex may be enhanced in this context. To identify genes that are required for alg-1(0) mutants to develop without vulval defects after dauer, we performed an RNAi screen of genes encoding conserved kinases. We focused on kinases because of their known role in modulating microRNA-induced silencing complex activity. We found RNAi knockdown of 4 kinase-encoding genes, air-2, bub-1, chk-1, and nekl-3, caused vulval defects and reiterative phenotypes in alg-1(0) mutants after dauer, and that these defects were more penetrant in an alg-1(0) background than in wild type. Our results implicate these kinases as potential regulators of microRNA-induced silencing complex activity during postdauer development in C. elegans.
Topics: Animals; Caenorhabditis elegans; MicroRNAs; RNA Interference; Caenorhabditis elegans Proteins; Argonaute Proteins; Gene Expression Regulation, Developmental; Mutation; RNA-Binding Proteins
PubMed: 38226857
DOI: 10.1093/g3journal/jkae007 -
Nucleic Acids Research Feb 2024MicroRNAs (miRNAs) guide Argonaute (AGO) proteins to bind mRNA targets. Although most targets are destabilized by miRNA-AGO binding, some targets induce degradation of... (Review)
Review
MicroRNAs (miRNAs) guide Argonaute (AGO) proteins to bind mRNA targets. Although most targets are destabilized by miRNA-AGO binding, some targets induce degradation of the miRNA instead. These special targets are also referred to as trigger RNAs. All triggers identified thus far have binding sites with greater complementarity to the miRNA than typical target sites. Target-directed miRNA degradation (TDMD) occurs when trigger RNAs bind the miRNA-AGO complex and recruit the ZSWIM8 E3 ubiquitin ligase, leading to AGO ubiquitination and proteolysis and subsequent miRNA destruction. More than 100 different miRNAs are regulated by ZSWIM8 in bilaterian animals, and hundreds of trigger RNAs have been predicted computationally. Disruption of individual trigger RNAs or ZSWIM8 has uncovered important developmental and physiologic roles for TDMD across a variety of model organisms and cell types. In this review, we highlight recent progress in understanding the mechanistic basis and functions of TDMD, describe common features of trigger RNAs, outline best practices for validating trigger RNAs, and discuss outstanding questions in the field.
Topics: Animals; Argonaute Proteins; Binding Sites; MicroRNAs; Proteolysis; Ubiquitination; RNA Stability
PubMed: 38224449
DOI: 10.1093/nar/gkae003 -
PloS One 2024Sinonasal tumours are heterogeneous malignancies, presenting different histological features and clinical behaviour. Many studies emphasize the role of specific miRNA in...
Sinonasal tumours are heterogeneous malignancies, presenting different histological features and clinical behaviour. Many studies emphasize the role of specific miRNA in the development and progression of cancer, and their expression profiles could be used as prognostic biomarkers to predict the survival. Recently, using the next-generation sequencing (NGS)-based miRNome analysis the miR-34/miR-449 cluster was identified as miRNA superfamily involved in the pathogenesis of sinonasal cancers (SNCs). In the present study, we established an Argonaute-2 (AGO2): mRNA immunoprecipitation followed by high-throughput sequencing to analyse the regulatory role of miR-34/miR-449 in SNCs. Using this approach, we identified direct target genes (targetome), which were involved in regulation of RNA-DNA metabolic, transcript and epigenetic processes. In particular, the STK3, C9orf78 and STRN3 genes were the direct targets of both miR-34c and miR-449a, and their regulation are predictive of tumour progression. This study provides the first evidence that miR-34/miR-449 and their targets are deregulated in SNCs and could be proposed as valuable prognostic biomarkers.
Topics: Argonaute Proteins; Biomarkers; MicroRNAs; Neoplasms; Paranasal Sinuses; Humans
PubMed: 38215077
DOI: 10.1371/journal.pone.0295997 -
Nature Communications Jan 2024Argonaute (Ago) proteins are ubiquitous across all kingdoms of life. Eukaryotic Agos (eAgos) use small RNAs to recognize transcripts for RNA silencing in eukaryotes. In...
Argonaute (Ago) proteins are ubiquitous across all kingdoms of life. Eukaryotic Agos (eAgos) use small RNAs to recognize transcripts for RNA silencing in eukaryotes. In contrast, the functions of prokaryotic counterparts (pAgo) are less well known. Recently, short pAgos in conjunction with the associated TIR or Sir2 (SPARTA or SPARSA) were found to serve as antiviral systems to combat phage infections. Herein, we present the cryo-EM structures of nicotinamide adenine dinucleotide (NAD)-bound SPARSA with and without nucleic acids at resolutions of 3.1 Å and 3.6 Å, respectively. Our results reveal that the APAZ (Analogue of PAZ) domain and the short pAgo form a featured architecture similar to the long pAgo to accommodate nucleic acids. We further identified the key residues for NAD binding and elucidated the structural basis for guide RNA and target DNA recognition. Using structural comparisons, molecular dynamics simulations, and biochemical experiments, we proposed a putative mechanism for NAD hydrolysis in which an H186 loop mediates nucleophilic attack by catalytic water molecules. Overall, our study provides mechanistic insight into the antiphage role of the SPARSA system.
Topics: NAD; RNA, Guide, CRISPR-Cas Systems; Argonaute Proteins; Bacteriophages; Nucleic Acids
PubMed: 38200015
DOI: 10.1038/s41467-023-44660-7 -
Nucleic Acids Research Mar 2024Argonaute (Ago) proteins are present in all three domains of life (bacteria, archaea and eukaryotes). They use small (15-30 nucleotides) oligonucleotide guides to bind...
Argonaute (Ago) proteins are present in all three domains of life (bacteria, archaea and eukaryotes). They use small (15-30 nucleotides) oligonucleotide guides to bind complementary nucleic acid targets and are responsible for gene expression regulation, mobile genome element silencing, and defence against viruses or plasmids. According to their domain organization, Agos are divided into long and short Agos. Long Agos found in prokaryotes (long-A and long-B pAgos) and eukaryotes (eAgos) comprise four major functional domains (N, PAZ, MID and PIWI) and two structural linker domains L1 and L2. The majority (∼60%) of pAgos are short pAgos, containing only the MID and inactive PIWI domains. Here we focus on the prokaryotic Argonaute AfAgo from Archaeoglobus fulgidus DSM4304. Although phylogenetically classified as a long-B pAgo, AfAgo contains only MID and catalytically inactive PIWI domains, akin to short pAgos. We show that AfAgo forms a heterodimeric complex with a protein encoded upstream in the same operon, which is a structural equivalent of the N-L1-L2 domains of long pAgos. This complex, structurally equivalent to a long PAZ-less pAgo, outperforms standalone AfAgo in guide RNA-mediated target DNA binding. Our findings provide a missing piece to one of the first and the most studied pAgos.
Topics: Archaeoglobus fulgidus; Argonaute Proteins; Bacteria; Eukaryota; Prokaryotic Cells; Protein Domains; RNA, Guide, CRISPR-Cas Systems; Archaeal Proteins
PubMed: 38197228
DOI: 10.1093/nar/gkad1241 -
Ecotoxicology and Environmental Safety Jan 2024Phthalates (PEs) are widely used plasticizers in polymer products, and humans are increasingly exposed to them. This study was designed to investigate the alleviative...
Phthalates (PEs) are widely used plasticizers in polymer products, and humans are increasingly exposed to them. This study was designed to investigate the alleviative effect of phytochemicals quercetin (Que) against male reproductive toxicity caused by the mixture of three commonly used PEs (MPEs), and further to explore the underlying mechanism. Forty-eight male SD rats were randomly and evenly divided into control group, Que group, MPEs group and MPEs+Que group (n = 12); The oral exposure doses of MPEs and Que were 450 mg/kg/d and 50 mg/kg/d, respectively. After 91 days of continuous intervention, compared with control group, the testes weight, epididymis weight, serum sex hormones, and anogenital distance were significantly decreased in MPEs group (P < 0.05); Testicular histopathological observation showed that all seminiferous tubules were atrophy, leydig cells were hyperplasia, spermatogenic cells growth were arrested in MPEs group. Ultrastructural observation of testicular germ cells showed that the edges of the nuclear membranes were indistinct, and the mitochondria were severely damaged with the cristae disrupted, decreased or even disappeared in MPEs group. Immunohistochemistry and Western blot analysis showed that testicular CYP11A1, CYP17A1 and 17β-HSD were up-regulated, while StAR, PIWIL1 and PIWIL2 were down-regulated in MPEs group (P < 0.05); However, the alterations of these parameters were restored in MPEs+Que group. The results indicated MPEs disturbed steroid hormone metabolism, and caused male reproductive injuries; whereas, Que could inhibit MPEs' male reproductive toxicity, which might relate to the restored regulation of steroid hormone metabolism.
Topics: Humans; Rats; Male; Animals; Quercetin; Rats, Sprague-Dawley; Testis; Gonadal Steroid Hormones; Steroids; Testosterone; Argonaute Proteins; Phthalic Acids
PubMed: 38171105
DOI: 10.1016/j.ecoenv.2023.115920