Search Results (148)

PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNAs initially identified in germline cells as genome guardians that silence transposable elements. Recent studies have expanded this view, revealing that piRNAs and PIWI proteins are broadly expressed in somatic tissues and participate in epigenetic and post-transcriptional gene regulation. This review systematically summarizes piRNA biogenesis and molecular mechanisms, with a focus on their functional diversification from germline to somatic cells. We detail piRNA dysregulation and its association with various human diseases, including cancer, cardiovascular disorders, neurodegenerative diseases, immune dysfunction, and reproductive disorders. By integrating recent findings, this review provides a comprehensive overview of piRNA-mediated regulatory networks and highlights their potential as novel biomarkers and therapeutic targets. Full article

Background/Objectives: piRNAs (PIWI-interacting RNAs) can significantly modify the expression of protein-coding genes by suppressing the translation process. The aim of this work was to computationally evaluate the potential interactions between piRNAs and the mRNA of the Klotho gene, as well as other genes involved in key metabolic pathways related to health and lifespan regulation. Methods: Bioinformatic analysis was conducted using the MirTarget program, which determines the quantitative characteristics of predicted nucleotide interactions between piRNAs and mRNA targets. Results: Several piRNAs (piR-44682, piR-1940042, piR-3008660, piR-3215034, piR-6885965, and piR-7980636) were predicted to bind within a single cluster of binding sites on the KL mRNA. In addition, piR-6890096 was predicted to interact with the KL mRNA through full complementarity. The mRNAs of AFF2, BCL2L11, CPT1A, DAZAP1, NDRG3, SKIDA1, WBP4, ZIC5, and ZSWIM6 were predicted to interact with piR-3215034 and piR-6885965, forming clusters of binding sites located in the 5′ untranslated region (5′UTR), coding sequence (CDS), and 3′ untranslated region (3′UTR). Additionally, piR-576442, piR-1501557, piR-1845735, piR-2069834, and piR-3029987 were predicted to bind only within the 3′UTR of FGF23 mRNA. These results suggest that piRNAs are potential regulators of KL and other genes involved in key metabolic processes. Conclusions: The findings provide a basis for further experimental validation of predicted piRNA–mRNA interactions and their possible roles in gene regulation. Full article

Background: Diminished ovarian reserve is characterized by a decrease in oocyte count and estrogen levels, which leads to infertility. The genetic and epigenetic mechanisms in MI to MII transition or complete MII phase in the oocyte maturation process estrogen receptor alpha and piRNA relationship were evaluated. Methods: This study analyzed 100 cumulus oophorous complex samples from normoresponder and DOR patients undergoing IVF, subdivided into metaphase I and metaphase II stages. To elucidate the ER-α, PIWIL3, piR-651, and piR-823 genes qRT-PCR was used and qualitative ER-α protein expressions were determined by immunohistochemistry. Pearson’s correlation analysis was utilized to evaluate the interactions between genes within each experimental group. Results: The DOR samples exhibited significant downregulation of ER-α gene and protein expression compared to the NOR controls. PIWIL3 gene, piR-651, and piR-823 expressions reduced in DOR MI and MII. Strong positive correlations among ER-α, PIWIL3, piR-651, and piR-823 were observed in NOR, whereas DOR showed weaker correlations and immunohistochemistry verified lower ER-α protein levels in DOR. Conclusions: The disruption of ER-α and piRNA-related gene networks in DOR may underlie the suboptimal maturation of oocytes, and monitoring ER-α, PIWIL3, piR-651, and piR-823 expressions could facilitate early determination of maturation stages and improve assessment of ovarian reserve. The potential for transposition to MII in NOR and DOR oocytes was observed in relation to the association between ER-α protein/gene expression and PIWIL3, which regulates ER-α. Moreover, piR-651 and piR-823, whose expressions depend on estrogen level, indirectly regulate oocyte maturation from MI to MII in both NOR and DOR epigenetically. We suggest that the MI and MII stages of oocytes could be determined earlier in NOR and DOR cases by controlling ER-α, PIWIL3, piR-651 and piR-823 expressions. These molecular markers indicate promise for diagnostic applications in reproductive medicine, warranting further validation in larger cohorts. Full article

Ovarian cancer (OC) remains the leading cause of death among gynecologic cancers. Most women diagnosed with OC at advanced stages eventually develop relapse and chemoresistance, leading to poor clinical outcomes. While piRNAs have emerged as critical regulators of gene expression and tumor biology, their specific roles in OC remain to be fully elucidated. This study integrated clinical and computational analyses to investigate the expression pattern and functional relevance of P-element-induced wimpy testis (PIWI)-interacting RNA-823 (piR-823) and its associated protein piwi-like RNA-mediated gene silencing 1 (PIWIL1)/DNA methyltransferase 3B (DNMT3B)/E-cadherin (CDH1) axis in OC tissues from 40 patients, with 20 non-cancer control samples. Expression profiling was performed using qPCR on OC and normal ovarian tissues, followed by correlation and regression analyses. Public databases, including GEPIA, TNM plot, and MethBank, were explored to validate gene expression, methylation status, and pathway enrichment. Our results revealed that piR-823, PIWIL1, and DNMT3B were significantly upregulated in OC tissues (p < 0.001, p = 0.009, and p < 0.001, respectively), and they correlated positively with each other and inversely with CDH1 expression. CDH2, OCT4, and NANOG were significantly upregulated (p = 0.011, p = 0.03, and p < 0.001, respectively), whereas CDH1 expression was significantly downregulated (p < 0.001) in OC tissues. In silico analyses supported DNMT3B-mediated CDH1 promoter methylation, epithelial–mesenchymal transition (EMT), and stemness pathway enrichment. Our integrated computational and clinical analyses indicate that the piR-823/PIWIL1/DNMT3B/CDH1 axis is a putative epigenetic regulator of EMT and cancer stemness in ovarian cancer. Additionally, piR-823 may serve as a promising prognostic biomarker and therapeutic target, offering novel insights into OC pathogenesis and treatment. Full article

Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID) arise from disruptions of molecular programmes that coordinate neurogenesis, synaptogenesis, and circuit maturation. While genomic studies have identified numerous susceptibility loci, genetic variation alone accounts for only part of disease heritability, underscoring the importance of post-transcriptional and epigenetic regulation. Among these regulatory layers, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), PIWI-interacting RNAs (piRNAs), and transfer RNA-derived small RNAs (tsRNAs), have emerged as central modulators of neural differentiation, synaptic plasticity, and intercellular signalling. Recent multi-omics and single-cell studies reveal that ncRNAs fine-tune chromatin accessibility, transcriptional output, and translation through tightly integrated regulatory networks. miRNAs shape neurogenic transitions and circuit refinement; lncRNAs and circRNAs couple chromatin architecture to activity-dependent transcription; and tsRNAs and piRNAs extend this regulation by linking translational control to epigenetic memory and environmental responsiveness. Spatial transcriptomics further maps ncRNA expression to vulnerable neuronal and glial subtypes across cortical and subcortical regions. Clinically, circulating ncRNAs, especially those packaged in extracellular vesicles, exhibit stable, disease-associated signatures, supporting their potential as minimally invasive biomarkers for early diagnosis and patient stratification. Parallel advances in RNA interference, antisense oligonucleotides, CRISPR-based editing, and vesicle-mediated delivery highlight emerging therapeutic opportunities. These developments position ncRNAs as both mechanistic determinants and translational targets in NDDs, offering a unifying framework that links genome regulation, environmental cues, and neural plasticity, and paving the way for next-generation RNA-guided diagnostics and therapeutics. Full article

Non-coding RNA (ncRNA) encompasses a large family of molecules that are crucial regulators of gene expression. This family includes microRNA, piwi-interacting RNA, and long non-coding RNA (lncRNA); each class is associated with different mechanisms of action that influence gene expression. Based on the available evidence, these molecules have important roles in physiological and pathological processes. For example, ncRNAs are strongly implicated in oncogenesis by mediating the expression of tumour suppressors and oncogenes. This review comprehensively describes the latest findings regarding the roles of lncRNAs in the pathophysiology of melanoma. Key aspects of melanoma biology and various mechanisms regulated by lncRNAs are discussed. Furthermore, future areas exploring potential biomarkers and therapeutic targets are presented. Full article

Background/Objectives: Hypertrophic scar (HS) is a fibroproliferative disorder characterized by excessive fibroblast activation and collagen deposition. The role of PIWI-interacting RNAs (piRNAs) in HS pathogenesis has not been defined. This study aimed to identify HS-related piRNAs, clarify their molecular mechanisms, and evaluate their therapeutic potential. Methods: High-throughput piRNA sequencing was performed on hypertrophic scar and matched normal tissues, followed by validation in patient-derived samples and dermal fibroblasts using quantitative reverse transcription PCR. Functional assays, including proliferation, apoptosis, migration, and invasion assays, were conducted after transfection with piRNA mimics or inhibitors. RNA sequencing, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, as well as dual-luciferase reporter and rescue assays, were used to identify and confirm molecular targets. Results: Sequencing revealed piR-hsa-022095 as one of the most significantly upregulated piRNAs in HS. Its inhibition suppressed fibroblast viability, migration, and invasion while inducing apoptosis and G₀/G₁ arrest. Transcriptomic profiling identified cell-cycle–related genes as major downstream targets, with KLF11 emerging as the principal effector. piR-hsa-022095 targets the 3′ UTR of KLF11, repressing its expression and thereby facilitating fibroblast proliferation. Restoration of KLF11 reversed the pro-fibrotic effects of piR-hsa-022095, confirming its functional role in HS pathogenesis. Conclusions: This study identifies piR-hsa-022095 as a novel regulator implicated in HS formation through repression of KLF11. The piR-hsa-022095–KLF11 axis may represent a previously unrecognized regulatory pathway involved in hypertrophic scar formation, providing new insights into the molecular mechanisms underlying HS pathogenesis. Full article

PIWI-interacting RNAs (piRNAs) are small non-coding RNAs that interact with PIWI proteins and play essential roles in genome stability, gonadal development, and gametogenesis in animals. The Japanese flounder (Paralichthys olivaceus) is an important marine culture teleost in North Asia, showing pronounced sexual size dimorphism, where gynogenetic induction of all-female cohorts can markedly enhance production. However, the PIWI/piRNA pathway in gynogenetic diploid P. olivaceus, which often exhibit gonadal dysgenesis, poor gamete quality, and low fertilization rates, remains poorly understood. In this study, RNA-seq and small RNA-seq data from 11 tissues and 6 developmental stages of common P. olivaceus, as well as the gonads of gynogenetic P. olivaceus, were analyzed to characterize the PIWI/piRNA pathway and its roles in transposon and gene regulation within the germline. The results showed that PIWI/piRNA genes were predominantly expressed in gonads and early embryogenesis in common P. olivaceus, with the highest expression in testis. Clustered piRNAs were identified in the testis and early embryos of common P. olivaceus, which targeted multiple transposon and gene families. Intriguingly, gynogenetic P. olivaceus gonads harbored abundant clustered piRNAs not only in the testes but also in the ovaries, both targeting similar transposon families as that in common P. olivaceus. Notably, the DNA transposon Tc1/Mariner family and pim genes were the most heavily targeted by piRNAs in gynogenetic P. olivaceus, with testis-biased expression. Expanded pim genes were identified in P. olivaceus, overlapping with piRNA clusters, and the in vitro test in P. olivaceus testes revealed that the expanded pim genes may be pseudogenes as a piRNA cluster reference to generate piRNAs regulating the conventional pim members. These unique features of the PIWI/piRNA pathway in gynogenetic diploid P. olivaceus may underline their impaired reproductive ability, and have important theoretical and practical implications for teleost gynogenetic breeding. Full article

Non-coding RNAs (ncRNAs) are critical regulators of gene expression, taking part in the modulation of multiple biological functions across a range of cell types. Initially dismissed as transcriptional noise, ncRNAs are now recognized for their significant roles in key cellular mechanisms, including differentiation, apoptosis, and proliferation, as well as their profound implications for the pathogenesis of numerous human diseases. Due to their remarkable stability, tissue-specific expression patterns, and abundance in body fluids, ncRNAs hold significant promise as non-invasive biomarkers for diagnosis, prognosis, and therapeutic monitoring. Furthermore, advances in RNA-targeted therapeutics have introduced novel strategies to modulate ncRNA activity, although challenges related to delivery efficiency, specificity, and clinical validation remain. This review comprehensively summarizes the classification, biogenesis, and molecular functions of ncRNAs, elucidates their involvement in health and disease, and evaluates their potential as clinical biomarkers and therapeutic targets. Additionally, it discusses the emerging technologies for RNA manipulation, including CRISPR-based RNA editing, that can advance ncRNA research and revolutionize ncRNA-based therapeutics. Full article

In Drosophila gonads, transposable elements (TEs) are repressed by the Piwi-interacting RNA (piRNA) pathway operating both co-transcriptionally and post-transcriptionally. In the non-gonadal tissues, TEs are mainly repressed by the short interfering RNA (siRNA) pathway with Argonaute 2 (Ago2) functioning as an effector protein. It is generally assumed that this pathway acts at the post-transcriptional level. However, recent data point to its possible involvement in co-transcriptional silencing as well. Here, using DamID, we found a drastic decrease in HP1a on TEs (especially on the LTR-containing retrotransposons) and other heterochromatin regions in Ago2-mutant Drosophila brain. HP1a reduction is accompanied by the increased chromatin accessibility of TEs, indicating their derepression. Accordingly, several LTR-containing retrotransposons were up-regulated in the larval brain of Ago2 mutants. Moreover, upon the knock-down of lamin Dm0 in neurons, HP1a was increased predominantly on the same set of TEs that had reduced HP1a binding in Ago2 mutants. We hypothesize that, since Ago2 was localized to the common complex with lamin Dm0, the depletion of the latter may release Ago2 in the nucleoplasm, thus enhancing the recruitment of HP1a on TEs. Our findings support the hypothesis that TEs in the Drosophila brain are silenced, in part, through Ago2-mediated recruitment of HP1a. Full article

Heart failure with preserved ejection fraction (HFpEF) represents a growing global public health challenge, now accounting for approximately half of all heart failure cases and often linked to a systemic pathophysiological process in older adults with multiple comorbidities. Despite increasing recognition of the vascular contributions to HFpEF, the precise molecular mechanisms, particularly the role of noncoding Ribonucleic Acids (ncRNAs) in mediating vascular aging and subsequent cardiac dysfunction, remain incompletely understood. This review provides a comprehensive overview of the mechanistic link between vascular aging and HFpEF, with a specific focus on the pivotal roles of ncRNAs in this complex interplay. We delineate the classification of vascular aging, its cellular hallmarks, including endothelial senescence, vascular smooth muscle cell phenotypic switching, and extracellular matrix remodeling, and its systemic implications, such as inflammaging, oxidative stress, and reduced nitric oxide bioavailability. We then detail how these vascular alterations, including increased ventricular afterload and impaired myocardial perfusion due to coronary microvascular dysfunction, contribute to HFpEF pathophysiology. The review extensively discusses recent findings on how diverse classes of ncRNAs, notably microRNAs, long noncoding RNAs, and circular RNAs, along with emerging evidence for PIWI-interacting RNAs, small nuclear RNAs, small nucleolar RNAs, and tRNA-derived small RNAs, regulate these vascular aging processes and serve as molecular bridges connecting vascular dysfunction to heart failure. In conclusion, understanding the regulatory landscape of ncRNAs in vascular aging may reveal novel biomarkers and therapeutic avenues, offering new strategies for precision medicine in HFpEF. Full article

Background: Neurodevelopmental disorders, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), are increasingly recognized as conditions arising from multifaceted interactions among genetic predisposition, environmental exposures, and epigenetic modifications. Among epigenetic mechanisms, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and PIWI-interacting RNAs (piRNAs), have gained attention as pivotal regulators of gene expression during neurodevelopment. These RNA species do not encode proteins but modulate gene expression at transcriptional and post-transcriptional levels, thereby influencing neuronal differentiation, synaptogenesis, and plasticity. Objectives: This systematic review critically examines and synthesizes the most recent findings, particularly in the post-COVID transcriptomic research era, regarding the role of ncRNAs in the pathogenesis, diagnosis, and potential treatment of neurodevelopmental disorders. Methods: A comprehensive literature search was conducted to identify studies reporting on the expression profiles, functional implications, and clinical relevance of ncRNAs in neurodevelopmental disorders, across both human and animal models. Results: Here, we highlight that multiple classes of ncRNAs are differentially expressed in individuals with ASD and ADHD. Notably, specific miRNAs and lncRNAs demonstrate potential as diagnostic biomarkers with high sensitivity and specificity. Functional studies further reveal that ncRNAs actively contribute to pathogenic mechanisms by modulating neuronal gene networks. Conclusions: Emerging experimental data indicate that the exogenous administration of certain ncRNAs may reverse molecular and behavioral phenotypes, supporting their therapeutic promise. These findings broaden our understanding of neurodevelopmental regulation and open new avenues for personalized diagnostics and targeted interventions in clinical neuropsychiatry. Full article

Protein functional effector (pfe)RNAs were introduced in 2015 as PIWI-interacting-like small noncoding (nc)RNAs and were later categorized as a novel group based on being 2′-O-methylated at their 3′-end, directly binding and affecting protein function, but not levels, and not matching known RNAs. Here, we document that human pfeRNAs match fragments of GenBank database-annotated human ncRNAs. PDLpfeRNAa matches the 3′-half fragment of a mitochondrial transfer (t)RNA, and PDLpfeRNAb matches a 28S ribosomal (r)RNA fragment. These PDLpfeRNAs are known to bind to tumor programmed death ligand (PD-L)1, enhancing or inhibiting its interaction with lymphocyte PD-1 and consequently tumor immune escape, respectively. In a validated 8-pfeRNA-set classifier for pulmonary nodule presence and benign vs. malignant nature, seven here match one or more of the following: transfer, micro, Y, PIWI, long (lnc)RNAs, and a PDLpfeRNAa fragment. The previously identified chromosomal locations of these pfeRNAs and their matches partially overlap. Another 2-pfeRNA set was previously determined to distinguish between controls, patients with pulmonary tuberculosis, and those with lung cancer. One pfeRNA, previously shown to bind p60-DMAD and affect apoptosis, complements small nucleolar RNA SNORD45C, matching smaller 18S rRNA and lncRNA segments. Thus, pfeRNAs appear to have a common origin with known multifunctional ncRNA fragments. Differential modification may contribute to the multifunctionality of ncRNAs. For instance, for tRNA fragments, stabilizing 3′-end 2′-O-methylation, 3′-aminoacylation, and glycosylation modifications may regulate protein function, translation, and extracellular effects, respectively. One ncRNA gene can encode multiple fragments, multiple genes can encode the same fragment, and differentially modified ncRNA fragments might synergize or antagonize each other. Full article

The selective regulation of gene expression at the RNA level represents a rapidly evolving field offering substantial clinical potential. This review examines the molecular mechanisms of intracellular enzymatic systems that utilize single-stranded nucleic acids to downregulate specific RNA targets. The analysis encompasses antisense oligonucleotides and synthetic mimics of small interfering RNA (siRNA), microRNA (miRNA), transfer RNA-derived small RNA (tsRNA), and PIWI-interacting RNA (piRNA), elucidating their intricate interactions with crucial cellular machinery, specifically RNase H1, RNase P, AGO, and PIWI proteins, mediating their biological effects. The functional and structural characteristics of these endonucleases are examined in relation to their mechanisms of action and resultant therapeutic outcomes. This comprehensive analysis illuminates the interactions between single-stranded nucleic acids and their endonuclease partners, covering antisense inhibition pathways as well as RNA interference processes. This field of research has important implications for advancing targeted RNA modulation strategies across various disease contexts. Full article

Epigenetics and genome science have become central to current molecular biology research. Among the key mechanisms ensuring genomic integrity is the silencing of transposable elements in germline cells, a process essential for fertility in both sexes. A pivotal component of this silencing machinery involves PIWI-interacting RNAs (piRNAs), a distinct class of small non-coding RNAs that regulate gene expression and suppress transposable elements at both the transcriptional and post-transcriptional levels. piRNAs function in concert with PIWI proteins, whose expression is critical for proper oogenesis, spermatogenesis, and early zygote development. Disruptions in piRNA or PIWI protein pathways not only impair germline function but also contribute to genome instability, unchecked cell proliferation, and aberrant epigenetic modifications, hallmarks of tumorigenesis. Emerging evidence links the dysregulation of the piRNA/PIWI axis to the development and progression of various cancers, including lung and colorectal carcinomas. This review highlights the fundamental roles of piRNAs and PIWI proteins in reproductive biology and their increasingly recognized relevance in cancer biology. Full article