Non-Coding RNA

20 pages, 15276 KiB

Open AccessArticle

In Silico Prioritization of STAT1 3′ UTR SNPs Identifies rs190542524 as a miRNA-Linked Variant with Potential Oncogenic Impact

by Ebtihal Kamal

Non-Coding RNA 2025, 11(3), 32; https://doi.org/10.3390/ncrna11030032 - 29 Apr 2025

Abstract

Background: Single-nucleotide polymorphisms (SNPs) are associated with multiple disorders and various cancer types. In the context of cancer, alterations within non-coding regions, specifically 3′ untranslated regions (3′ UTR), have proven substantially important. Methods: In this study, we utilized various bioinformatics tools to examine [...] Read more.

Background: Single-nucleotide polymorphisms (SNPs) are associated with multiple disorders and various cancer types. In the context of cancer, alterations within non-coding regions, specifically 3′ untranslated regions (3′ UTR), have proven substantially important. Methods: In this study, we utilized various bioinformatics tools to examine the effect of SNPs in the 3′ UTR. We retrieved the 3′ UTR SNPs of the Signal Transducer and Activator of Transcription 1 (STAT1) gene from the National Centre for Biotechnology Information (NCBI) website. Next, we employed the Polymorphism in miRNAs and their corresponding target sites (PolymiRTS) database to predict the 3′ UTR SNPs that create new microRNA (miRNA) binding sites and their respective miRNAs. The effect of the 3′ UTR SNPs on the messenger RNA structure was studied using RNAfold server. We used Cscape tool to predict the oncogenic 3′ UTR SNPs. Then, we submitted the miRNAs to the miRNet database to visualize the miRNA-miRNAs’ target genes interaction, for which gene enrichment analysis was performed using ShinyGO. Protein–protein interactions were conducted using the STRING database. We conducted miRNA enrichment analysis utilizing miRPathDB, subsequently performing miRNA differential expression analysis through oncoMIR, and the StarBase database. The survival analysis of the upregulated miRNAs in cancer was investigated using the Kaplan–Meier Plotter. Result: Twelve SNPs were predicted to create new miRNA binding sites. Two of them, rs188557905 and rs190542524, were predicted to destabilize the mRNA structures. We predicted rs190542524, rs11305, rs186033487, and rs188557905 to be oncogenic 3′ UTR SNPs, with high-confidence predictions and scores > 0.5. Using miRNAs’ target genes enrichment analysis, this study indicated that the miRNA target genes were more likely to be involved in cancer-related pathways. Our comprehensive analysis of miRNAs, their functional enrichment, their expression in various types of cancer, and the correlation between miRNA expression and survival outcome yielded these results. Our research shows that the oncogenic 3′ UTR SNP rs190542524 creates a new binding site for the oncogenic miRNA hsa-miR-136-5p. This miRNA is significantly upregulated in BLCA, LUSC, and STAD and is linked to poor survival. Additionally, rs114360225 creates a new binding site for hsa-miR-362-3p, influencing LIHC. Conclusions: These analyses suggest that these 3′ UTR SNPs may have a functional impact on the STAT1 gene’s regulation through their predicted effect on miRNA binding sites. Future experimental validation could establish their potential role in the diagnosis and treatment of various diseases, including cancer. Full article

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28 pages, 7091 KiB

Open AccessArticle

Role of Long Non-Coding RNA X-Inactive-Specific Transcript (XIST) in Neuroinflammation and Myelination: Insights from Cerebral Organoids and Implications for Multiple Sclerosis

by Nihan Aktas Pepe, Busra Acar, Gozde Erturk Zararsiz, Serife Ayaz Guner and Alaattin Sen

Non-Coding RNA 2025, 11(3), 31; https://doi.org/10.3390/ncrna11030031 - 29 Apr 2025

Abstract

Background/Objectives: X-inactive-specific transcript (XIST) is a factor that plays a role in neuroinflammation. This study investigated the role of XIST in neuronal development, neuroinflammation, myelination, and therapeutic responses within cerebral organoids in the context of Multiple Sclerosis (MS) pathogenesis. Methods [...] Read more.

Background/Objectives: X-inactive-specific transcript (XIST) is a factor that plays a role in neuroinflammation. This study investigated the role of XIST in neuronal development, neuroinflammation, myelination, and therapeutic responses within cerebral organoids in the context of Multiple Sclerosis (MS) pathogenesis. Methods: Human cerebral organoids with oligodendrocytes were produced from XIST-silenced H9 cells, and the mature organoids were subsequently treated with either FTY720 or DMF. Gene expression related to inflammation and myelination was subsequently analyzed via qRT-PCR. Immunofluorescence staining was used to assess the expression of proteins related to inflammation, myelination, and neuronal differentiation. Alpha-synuclein protein levels were also checked via ELISA. Finally, transcriptome analysis was conducted on the organoid samples. Results: XIST-silenced organoids presented a 2-fold increase in the expression of neuronal stem cells, excitatory neurons, microglia, and mature oligodendrocyte markers. In addition, XIST silencing increased IL-10 mRNA expression by 2-fold and MBP and PLP1 expression by 2.3- and 0.6-fold, respectively. Although XIST silencing tripled IBA1 protein expression, it did not affect organoid MBP expression. FTY720, but not DMF, distinguished MBP and IBA1 expression in XIST-silenced organoids. Furthermore, XIST silencing reduced the concentration of alpha-synuclein from 300 to 100 pg/mL, confirming its anti-inflammatory role. Transcriptomic and gene enrichment analyses revealed that the differentially expressed genes are involved in neural development and immune processes, suggesting the role of XIST in neuroinflammation. The silencing of XIST modified the expression of genes associated with inflammation, myelination, and neuronal growth in cerebral organoids, indicating a potential involvement in the pathogenesis of MS. Conclusions: XIST may contribute to the MS pathogenesis as well as neuroinflammatory diseases such as and Alzheimer’s and Parkinson’s diseases and may be a promising therapeutic target. Full article

(This article belongs to the Section Long Non-Coding RNA)

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26 pages, 1665 KiB

Open AccessReview

Role of Non-Coding RNAs in White and Brown Adipose Tissue Differentiation and Development

by Lea Sleiman and Sorina Dinescu

Non-Coding RNA 2025, 11(3), 30; https://doi.org/10.3390/ncrna11030030 - 29 Apr 2025

Abstract

Adipocyte differentiation is a complex process in which pluripotent mesenchymal stem cells (MSCs) differentiate and develop into mature fat cells, also known as adipocytes. This process is controlled by various transcription factors, hormones, and signaling molecules that regulate the development of these cells. [...] Read more.

Adipocyte differentiation is a complex process in which pluripotent mesenchymal stem cells (MSCs) differentiate and develop into mature fat cells, also known as adipocytes. This process is controlled by various transcription factors, hormones, and signaling molecules that regulate the development of these cells. Recently, an increasing number of non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), have been established to be involved in the regulation of many biological processes, including adipocyte differentiation, development, metabolism, and energy homeostasis of white and brown adipose tissue. Several in vitro and in vivo studies reported the significant role of ncRNAs in either promoting or inhibiting adipocyte differentiation into white or brown fat cells by targeting specific transcription factors and regulating the expression of key adipogenic genes. Identifying the function of ncRNAs and their subsequent targets contributes to our understanding of how these molecules can be used as potential biomarkers and tools for therapies against obesity, diabetes, and other diseases related to obesity. This could also contribute to advancements in tissue-engineering based treatments. In this review, we intended to present an up-to-date comprehensive literature overview of the role of ncRNAs, including miRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), focusing particularly on miRNAs, in regulating the differentiation and development of cells into white and brown adipose tissue. In addition, we further discuss the potential use of these molecules as biomarkers for the development of novel therapeutic strategies for future personalized treatment options for patients. Full article

(This article belongs to the Special Issue Non-coding RNAs in Stem Cell Differentiation and Disease)

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15 pages, 656 KiB

Open AccessReview

The Role of Long Non-Coding RNAs in Human Endoderm Differentiation

by Annanda Lyra Ribeiro and Bruno Dallagiovanna

Non-Coding RNA 2025, 11(2), 29; https://doi.org/10.3390/ncrna11020029 - 13 Apr 2025

Abstract

The human genome sequencing revealed a vast complexity of transcripts, with over 80% of the genome being transcribed into non-coding RNAs. In particular, long non-coding RNAs (lncRNAs) have emerged as critical regulators of various cellular processes, including embryonic development and stem cell differentiation. [...] Read more.

The human genome sequencing revealed a vast complexity of transcripts, with over 80% of the genome being transcribed into non-coding RNAs. In particular, long non-coding RNAs (lncRNAs) have emerged as critical regulators of various cellular processes, including embryonic development and stem cell differentiation. Despite extensive efforts to identify and characterize lncRNAs, defining their mechanisms of action in state-specific cellular contexts remains a significant challenge. Only recently has the involvement of lncRNAs in human endoderm differentiation of pluripotent stem cells begun to be addressed, creating an opportunity to explore the mechanisms by which lncRNAs exert their functions in germ layer formation, lineage specification, and commitment. This review summarizes current findings on the roles of lncRNAs in endoderm differentiation, highlighting the functional mechanisms and regulatory aspects underlying their involvement in cell fate decisions leading to endoderm development. The key lncRNAs implicated in endoderm differentiation are discussed, along with their interaction with transcription factors and RNA-binding proteins and modulation of signaling pathways essential for endoderm development. Gaining insight into the regulatory roles of lncRNAs in endoderm differentiation enhances the understanding of developmental biology and provides a foundation for discovering novel lncRNAs involved in cell fate determination. Full article

(This article belongs to the Section Long Non-Coding RNA)

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20 pages, 1899 KiB

Open AccessReview

Decoding Salivary ncRNAomes as Novel Biomarkers for Oral Cancer Detection and Prognosis

by Subhadeep Das, Sampad Basak and Soumyadev Sarkar

Non-Coding RNA 2025, 11(2), 28; https://doi.org/10.3390/ncrna11020028 - 20 Mar 2025

Abstract

Oral cancer (OC) ranks among the most prevalent head and neck cancers, becoming the eleventh most common cancer worldwide with ~350,000 new cases and 177,000 fatalities annually. The rising trend in the occurrence of OC among young individuals and women who do not [...] Read more.

Oral cancer (OC) ranks among the most prevalent head and neck cancers, becoming the eleventh most common cancer worldwide with ~350,000 new cases and 177,000 fatalities annually. The rising trend in the occurrence of OC among young individuals and women who do not have tobacco habits is escalating rapidly. Surgical procedures, radiation therapy, and chemotherapy are among the most prevalent treatment options for oral cancer. To achieve better therapy and an early detection of the cancer, it is essential to understand the disease’s etiology at the molecular level. Saliva, the most prevalent body fluid obtained non-invasively, holds a collection of distinct non-coding RNA pools (ncRNAomes) that can be assessed as biomarkers for identifying oral cancer. Non-coding signatures, which are transcripts lacking a protein-coding function, have been identified as significant in the progression of various cancers, including oral cancer. This review aims to examine the role of various salivary ncRNAs (microRNA, circular RNA, and lncRNA) associated with disease progression and to explore their functions as potential biomarkers for early disease identification to ensure better survival outcomes for oral cancer patients. Full article

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17 pages, 1363 KiB

Open AccessReview

The Role of Non-Coding RNAs in MYC-Mediated Metabolic Regulation: Feedback Loops and Interactions

by Aliaa Amr Alamoudi

Non-Coding RNA 2025, 11(2), 27; https://doi.org/10.3390/ncrna11020027 - 18 Mar 2025

Abstract

Metabolic reprogramming is a hallmark of cancer, crucial for supporting the rapid energy demands of tumor cells. MYC, often deregulated and overexpressed, is a key driver of this shift, promoting the Warburg effect by enhancing glycolysis. However, there remains a gap in understanding [...] Read more.

Metabolic reprogramming is a hallmark of cancer, crucial for supporting the rapid energy demands of tumor cells. MYC, often deregulated and overexpressed, is a key driver of this shift, promoting the Warburg effect by enhancing glycolysis. However, there remains a gap in understanding the mechanisms and factors influencing MYC’s metabolic roles. Recently, non-coding RNAs (ncRNAs) have emerged as important modulators of MYC functions. This review focuses on ncRNAs that regulate MYC-driven metabolism, particularly the Warburg effect. The review categorizes these ncRNAs into three main groups based on their interaction with MYC and examines the mechanisms behind these interactions. Additionally, we explore how different types of ncRNAs may collaborate or influence each other’s roles in MYC regulation and metabolic function, aiming to identify biomarkers and synthetic lethality targets to disrupt MYC-driven metabolic reprogramming in cancer. Finaly, the review highlights the clinical implications of these ncRNAs, providing an up-to-date summary of their potential roles in cancer prognosis and therapy. With the recent advances in MYC-targeted therapy reaching clinical trials, the exciting potential of combining these therapies with ncRNA-based strategies holds great promise for enhancing treatment efficacy. Full article

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20 pages, 2390 KiB

Open AccessArticle

A miRNA Signature for Non-Invasive Colorectal Cancer Diagnosis in Morocco: miR-21, miR-29a and miR-92a

by Sofia Fathi, Oussama Aazzane, Salma Guendaoui, Nezha Tawfiq, Souha Sahraoui, Fadila Guessous and Mehdi Karkouri

Non-Coding RNA 2025, 11(2), 26; https://doi.org/10.3390/ncrna11020026 - 17 Mar 2025

Abstract

Colorectal cancer (CRC) is the third most diagnosed cancer and a leading cause of cancer-related mortality in Morocco, often detected at late stages. Circulating microRNAs (miRNAs) have emerged as promising non-invasive biomarkers for CRC detection, with miR-21, miR-29a, and miR-92a showing significant diagnostic [...] Read more.

Colorectal cancer (CRC) is the third most diagnosed cancer and a leading cause of cancer-related mortality in Morocco, often detected at late stages. Circulating microRNAs (miRNAs) have emerged as promising non-invasive biomarkers for CRC detection, with miR-21, miR-29a, and miR-92a showing significant diagnostic potential. This study aimed to evaluate the expression levels of these miRNAs in a Moroccan population and their efficacy as diagnostic biomarkers. Methods: A prospective study was conducted using blood samples from 50 CRC patients and 50 healthy controls. Circulating miRNA expression levels were quantified through reverse transcription quantitative PCR (RT-qPCR), with normalization to miR-1228-3p. Statistical analyses, including the Mann–Whitney U test, Receiver Operating Characteristic (ROC) curve analysis, sensitivity (Sen), and specificity (Spe) evaluations, were performed to assess the diagnostic accuracy of individual miRNAs and their combined performance as panels. Results: The expression levels of miR-21, miR-29a, and miR-92a were significantly elevated in CRC patients compared to healthy controls (all p < 0.001). ROC analysis demonstrated that miR-92a exhibited the highest individual diagnostic performance (AUC: 0.938), followed by miR-21 (AUC: 0.907) and miR-29a (AUC: 0.898). Sensitivity and specificity were 88% and 90%, 92% and 56%, and 76% and 94%, respectively. Combinatorial analysis revealed that the miR-29a and miR-92a panel achieved the highest diagnostic accuracy (AUC: 0.976), surpassing individual miRNAs and other combinations, highlighting its potential as a robust, non-invasive biomarker panel for CRC. Conclusions: This study highlights the potential of the miR-29a and miR-92a combination, which achieved excellent diagnostic efficiency (AUC: 0.976). These findings underscore miRNA utility in enhancing early detection and reducing CRC-related mortality in Morocco. Full article

(This article belongs to the Special Issue Non-coding RNA as Biomarker in Cancer)

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9 pages, 1035 KiB

Open AccessCommunication

Chromatin Structure Around Long Non-Coding RNA (lncRNA) Genes in Schistosoma mansoni Gonads

by Ronaldo C. Augusto, Thomas Quack, Christoph G. Grevelding and Christoph Grunau

Non-Coding RNA 2025, 11(2), 25; https://doi.org/10.3390/ncrna11020025 - 12 Mar 2025

Abstract

In this study, we employed a total of eight distinct modifications of histone proteins (H3K23ac, H3K27me3, H3K36me3, H3K4me3, H3K9ac, H3K9me3, H4K12ac, and H4K20me1) to discern the various chromatin colors encompassing lncRNA genes in both mature and immature gonads of the human parasite Schistosoma [...] Read more.

In this study, we employed a total of eight distinct modifications of histone proteins (H3K23ac, H3K27me3, H3K36me3, H3K4me3, H3K9ac, H3K9me3, H4K12ac, and H4K20me1) to discern the various chromatin colors encompassing lncRNA genes in both mature and immature gonads of the human parasite Schistosoma mansoni. Our investigation revealed that these chromatin colors exhibit a tendency to aggregate based on the similarities in their metagene shapes, leading to the formation of less than six distinct clusters. Moreover, these clusters can be further grouped according to their resemblances by shape, which are co-linear with specific regions of the genes, and potentially associated with transcriptional stages. Full article

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21 pages, 1415 KiB

Open AccessReview

Single-Cell Transcriptomic Approaches for Decoding Non-Coding RNA Mechanisms in Colorectal Cancer

by Mahnoor Naseer Gondal and Hafiz Muhammad Umer Farooqi

Non-Coding RNA 2025, 11(2), 24; https://doi.org/10.3390/ncrna11020024 - 10 Mar 2025

Abstract

Non-coding RNAs (ncRNAs) play crucial roles in colorectal cancer (CRC) development and progression. Recent developments in single-cell transcriptome profiling methods have revealed surprising levels of expression variability among seemingly homogeneous cells, suggesting the existence of many more cell types than previously estimated. This [...] Read more.

Non-coding RNAs (ncRNAs) play crucial roles in colorectal cancer (CRC) development and progression. Recent developments in single-cell transcriptome profiling methods have revealed surprising levels of expression variability among seemingly homogeneous cells, suggesting the existence of many more cell types than previously estimated. This review synthesizes recent advances in ncRNA research in CRC, emphasizing single-cell bioinformatics approaches for their analysis. We explore computational methods and tools used for ncRNA identification, characterization, and functional prediction in CRC, with a focus on single-cell RNA sequencing (scRNA-seq) data. The review highlights key bioinformatics strategies, including sequence-based and structure-based approaches, machine learning applications, and multi-omics data integration. We discuss how these computational techniques can be applied to analyze differential expression, perform functional enrichment, and construct regulatory networks involving ncRNAs in CRC. Additionally, we examine the role of bioinformatics in leveraging ncRNAs as diagnostic and prognostic biomarkers for CRC. We also discuss recent scRNA-seq studies revealing ncRNA heterogeneity in CRC. This review aims to provide a comprehensive overview of the current state of single-cell bioinformatics in ncRNA CRC research and outline future directions in this rapidly evolving field, emphasizing the integration of computational approaches with experimental validation to advance our understanding of ncRNA biology in CRC. Full article

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26 pages, 2988 KiB

Open AccessArticle

A Multi-Input Neural Network Model for Accurate MicroRNA Target Site Detection

by Mohammad Mohebbi, Amirhossein Manzourolajdad, Ethan Bennett and Phillip Williams

Non-Coding RNA 2025, 11(2), 23; https://doi.org/10.3390/ncrna11020023 - 7 Mar 2025

Abstract

(1) Background: MicroRNAs are non-coding RNA sequences that regulate cellular functions by targeting messenger RNAs and inhibiting protein synthesis. Identifying their target sites is vital to understanding their roles. However, it is challenging due to the high cost and time demands of experimental [...] Read more.

(1) Background: MicroRNAs are non-coding RNA sequences that regulate cellular functions by targeting messenger RNAs and inhibiting protein synthesis. Identifying their target sites is vital to understanding their roles. However, it is challenging due to the high cost and time demands of experimental methods and the high false-positive rates of computational approaches. (2) Methods: We introduce a Multi-Input Neural Network (MINN) algorithm that integrates diverse biologically relevant features, including the microRNA duplex structure, substructures, minimum free energy, and base-pairing probabilities. For each feature derived from a microRNA target-site duplex, we create a corresponding image. These images are processed in parallel by the MINN algorithm, allowing it to learn a comprehensive and precise representation of the underlying biological mechanisms. (3) Results: Our method, on an experimentally validated test set, detects target sites with an AUPRC of 0.9373, Precision of 0.8725, and Recall of 0.8703 and outperforms several commonly used computational methods of microRNA target-site predictions. (4) Conclusions: Incorporating diverse biologically explainable features, such as duplex structure, substructures, their MFEs, and binding probabilities, enables our model to perform well on experimentally validated test data. These features, rather than nucleotide sequences, enhance our model to generalize beyond specific sequence contexts and perform well on sequentially distant samples. Full article

(This article belongs to the Topic MicroRNA: Mechanisms of Action, Physio-Pathological Implications, and Disease Biomarkers, 3rd Edition)

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24 pages, 3439 KiB

Open AccessReview

Mechanism of Action of circRNA/miRNA Network in DLBCL

by Elena Golovina, Cory Eaton, Virginia Cox, Jozef Andel and Karina Savvulidi Vargova

Non-Coding RNA 2025, 11(2), 22; https://doi.org/10.3390/ncrna11020022 - 4 Mar 2025

Abstract

Circular RNAs (circRNAs) make up approximately 10% of the human transcriptome. CircRNAs belong to the broad group of non-coding RNAs and characteristically are formed by backsplicing into a stable circular loop. Their main role is to regulate transcription through the inhibition of miRNAs’ [...] Read more.

Circular RNAs (circRNAs) make up approximately 10% of the human transcriptome. CircRNAs belong to the broad group of non-coding RNAs and characteristically are formed by backsplicing into a stable circular loop. Their main role is to regulate transcription through the inhibition of miRNAs’ expression, termed miRNA sponging. CircRNAs promote tumorigenesis/lymphomagenesis by competitively binding to miRNAs at miRNA binding sites. In diffuse large B-cell lymphoma (DLBCL), several circRNAs have been identified and their expression is related to both progression and response to therapy. DLBCL is the most prevalent and aggressive subtype of B-cell lymphomas and accounts for about 25% to 30% of all non-Hodgkin lymphomas. DLBCL displays great heterogeneity concerning histopathology, biology, and genetics. Patients who have relapsed or have refractory disease after first-line therapy have a very poor prognosis, demonstrating an important unmet need for new treatment options. As more circRNAs are identified in the future, we will better understand their biological roles and potential use in treating cancer, including DLBCL. For example, circAmotl1 promotes nuclear translocation of MYC and upregulation of translational targets of MYC, thus enhancing lymphomagenesis. Another example is circAPC, which is significantly downregulated in DLBCL and correlates with disease aggressiveness and poor prognosis. CircAPC increases expression of the host gene adenomatous polyposis coli (APC), and in doing so inactivates the canonical Wnt/β-catenin signaling and restrains DLBCL growth. MiRNAs belong to the non-coding regulatory molecules that significantly contribute to lymphomagenesis through their target mRNAs. In DLBCL, among the highly expressed miRNAs, are miR-155-5p and miR-21-5p, which regulate NF-ĸB and PI3K/AKT signaling pathways. The aim of this review is to describe the function and mechanism of regulation of circRNAs on miRNAs’ expression in DLBCL. This will help us to better understand the regulatory network of circRNA/miRNA/mRNA, and to propose novel therapeutic targets to treat DLBCL. Full article

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14 pages, 978 KiB

Open AccessReview

MicroRNAs: A Novel Approach for Monitoring Treatment Response in Major Depressive Disorder?

by Cristina-Sorina Cătană, Monica Mihaela Marta, Daniel Ungureanu and Cătălina-Angela Crișan

Non-Coding RNA 2025, 11(2), 21; https://doi.org/10.3390/ncrna11020021 - 3 Mar 2025

Abstract

Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders, with an increasing incidence each year and an important socioeconomic burden. Although new treatments are continuously being developed, there is no effective monitoring method to determine the suitability of treatment and [...] Read more.

Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders, with an increasing incidence each year and an important socioeconomic burden. Although new treatments are continuously being developed, there is no effective monitoring method to determine the suitability of treatment and ensure positive outcomes. Therefore, patients often struggle with ineffective antidepressants and their potential adverse effects, which halts any future progress in managing the disorder. Considering the potential of microRNAs (miRNAs) as biomarkers for various pathologies and the increasing evidence of the modulation of several genes involved in MDD, this minireview aimed to evaluate the literature data on the impact of miRNAs in MDD and their usefulness in monitoring treatment response. The correlations between antidepressants and the expression of several miRNAs support the existence of a common epigenetic mechanism of antidepressants and explain the epigenetic differences influencing treatment efficacy in MDD. Full article

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26 pages, 8550 KiB

Open AccessReview

The Unpaved Road of Non-Coding RNA Structure–Function Relationships: Current Knowledge, Available Methodologies, and Future Trends

by Ana Lúcia Leitão and Francisco J. Enguita

Non-Coding RNA 2025, 11(2), 20; https://doi.org/10.3390/ncrna11020020 - 2 Mar 2025

Abstract

The genomes from complex eukaryotes are enriched in non-coding genes whose transcription products (non-coding RNAs) are involved in the regulation of genomic output at different levels. Non-coding RNA action is predominantly driven by sequence and structural motifs that interact with specific functional partners. [...] Read more.

The genomes from complex eukaryotes are enriched in non-coding genes whose transcription products (non-coding RNAs) are involved in the regulation of genomic output at different levels. Non-coding RNA action is predominantly driven by sequence and structural motifs that interact with specific functional partners. Despite the exponential growth in primary RNA sequence data facilitated by next-generation sequencing studies, the availability of tridimensional RNA data is comparatively more limited. The subjacent reasons for this relative lack of information regarding RNA structure are related to the specific chemical nature of RNA molecules and the limitations of the currently available methods for structural characterization of biomolecules. In this review, we describe and analyze the different structural motifs involved in non-coding RNA function and the wet-lab and computational methods used to characterize their structure–function relationships, highlighting the current need for detailed structural studies to explore the molecular determinants of non-coding RNA function. Full article

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Graphical abstract

37 pages, 2513 KiB

Open AccessReview

The Emerging Applications of Artificial MicroRNA-Mediated Gene Silencing in Plant Biotechnology

by Luis Alberto Bravo-Vázquez, Ana Marta Castro-Pacheco, Rodrigo Pérez-Vargas, Joceline Fernanda Velázquez-Jiménez and Sujay Paul

Non-Coding RNA 2025, 11(2), 19; https://doi.org/10.3390/ncrna11020019 - 2 Mar 2025

Abstract

Improving crop yield potential is crucial to meet the increasing demands of a rapidly expanding global population in an ever-changing and challenging environment. Therefore, different technological approaches have been proposed over the last decades to accelerate plant breeding. Among them, artificial microRNAs (amiRNAs) [...] Read more.

Improving crop yield potential is crucial to meet the increasing demands of a rapidly expanding global population in an ever-changing and challenging environment. Therefore, different technological approaches have been proposed over the last decades to accelerate plant breeding. Among them, artificial microRNAs (amiRNAs) represent an innovative tool with remarkable potential to assist plant improvement. MicroRNAs (miRNAs) are a group of endogenous, small (20–24 nucleotides), non-coding RNA molecules that play a crucial role in gene regulation. They are associated with most biological processes of a plant, including reproduction, development, cell differentiation, biotic and abiotic stress responses, metabolism, and plant architecture. In this context, amiRNAs are synthetic molecules engineered to mimic the structure and function of endogenous miRNAs, allowing for the targeted silencing of specific nucleic acids. The current review explores the diverse applications of amiRNAs in plant biology and agriculture, such as the management of infectious agents and pests, the engineering of plant metabolism, and the enhancement of plant resilience to abiotic stress. Moreover, we address future perspectives on plant amiRNA-based gene silencing strategies, highlighting the need for further research to fully comprehend the potential of this technology and to translate its scope toward the widespread adoption of amiRNA-based strategies for plant breeding. Full article

(This article belongs to the Special Issue Non-Coding RNA and Their Regulatory Roles in Plant)

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21 pages, 2954 KiB

Open AccessArticle

Secondary-Structure-Informed RNA Inverse Design via Relational Graph Neural Networks

by Amirhossein Manzourolajdad and Mohammad Mohebbi

Non-Coding RNA 2025, 11(2), 18; https://doi.org/10.3390/ncrna11020018 - 26 Feb 2025

Abstract

RNA inverse design is an essential part of many RNA therapeutic strategies. To date, there have been great advances in computationally driven RNA design. The current machine learning approaches can predict the sequence of an RNA given its 3D structure with acceptable accuracy [...] Read more.

RNA inverse design is an essential part of many RNA therapeutic strategies. To date, there have been great advances in computationally driven RNA design. The current machine learning approaches can predict the sequence of an RNA given its 3D structure with acceptable accuracy and at tremendous speed. The design and engineering of RNA regulators such as riboswitches, however, is often more difficult, partly due to their inherent conformational switching abilities. Although recent state-of-the-art models do incorporate information about the multiple structures that a sequence can fold into, there is great room for improvement in modeling structural switching. In this work, a relational geometric graph neural network is proposed that explicitly incorporates alternative structures to predict an RNA sequence. Converting the RNA structure into a geometric graph, the proposed model uses edge types to distinguish between the primary structure, secondary structure, and spatial positioning of the nucleotides in representing structures. The results show higher native sequence recovery rates over those of gRNAde across different test sets (eg. 72% vs. 66%) and a benchmark from the literature (60% vs. 57%). Secondary-structure edge types had a more significant impact on the sequence recovery than the spatial edge types as defined in this work. Overall, these results suggest the need for more complex and case-specific characterization of RNA for successful inverse design. Full article

(This article belongs to the Special Issue RNA Meets AI: How Artificial Intelligence Can Boost the Discovery and Functional Characterization of Coding and Non-Coding RNAs)

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14 pages, 8695 KiB

Open AccessArticle

Combinatorial Analysis of miRNAs and tRNA Fragments as Potential Biomarkers for Cancer Patients in Liquid Biopsies

by Ilias Glogovitis, Silvia D’Ambrosi, Mafalda Antunes-Ferreira, Monica Chiogna, Galina Yahubyan, Vesselin Baev, Thomas Wurdinger and Danijela Koppers-Lalic

Non-Coding RNA 2025, 11(1), 17; https://doi.org/10.3390/ncrna11010017 - 14 Feb 2025

Abstract

Background: Liquid biopsy has gained significant attention as a non-invasive method for cancer detection and monitoring. IsomiRs and tRNA-derived fragments (tRFs) are small non-coding RNAs that arise from non-canonical microRNA (miRNAs) processing and the cleavage of tRNAs, respectively. These small non-coding RNAs have [...] Read more.

Background: Liquid biopsy has gained significant attention as a non-invasive method for cancer detection and monitoring. IsomiRs and tRNA-derived fragments (tRFs) are small non-coding RNAs that arise from non-canonical microRNA (miRNAs) processing and the cleavage of tRNAs, respectively. These small non-coding RNAs have emerged as pro-mising cancer biomarkers, and their distinct expression patterns highlight the need for further exploration of their roles in cancer research. Methods: In this study, we investigated the differential expression profiles of miRNAs, isomiRs, and tRFs in plasma extracellular vesicles (EVs) from colorectal and prostate cancer patients compared to healthy controls. Subsequently, a combinatorial analysis using the CombiROC package was performed to identify a panel of biomarkers with optimal diagnostic accuracy. Results: Our results demonstrate that a combination of miRNAs, isomiRs, and tRFs can effectively di- stinguish cancer patients from healthy controls, achieving accuracy and an area under the curve (AUC) of approximately 80%. Conclusions: These findings highlight the potential of a combinatorial approach to small RNA analysis in liquid biopsies for improved cancer diagnosis and management. Full article

(This article belongs to the Special Issue Extracellular Vesicles and ncRNA)

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25 pages, 881 KiB

Open AccessReview

Psoriasis Treatments: Emerging Roles and Future Prospects of MicroRNAs

by Li Tian Keane Teo, Nerissa Juantuah-Kusi, Gowtham Subramanian and Prabha Sampath

Non-Coding RNA 2025, 11(1), 16; https://doi.org/10.3390/ncrna11010016 - 13 Feb 2025

Abstract

Psoriasis, a widespread and chronic inflammatory skin disorder, is marked by its persistence and the lack of a definitive cure. The pathogenesis of psoriasis is increasingly understood, with ongoing research highlighting the intricate interplay of genetic, immunological, and environmental factors. Recent advancements have [...] Read more.

Psoriasis, a widespread and chronic inflammatory skin disorder, is marked by its persistence and the lack of a definitive cure. The pathogenesis of psoriasis is increasingly understood, with ongoing research highlighting the intricate interplay of genetic, immunological, and environmental factors. Recent advancements have illuminated the pivotal role of microRNAs in orchestrating complex processes in psoriasis and other hyperproliferative skin diseases. This narrative review highlights the emerging significance of miRNAs as key regulators in psoriasis pathogenesis and examines their potential as therapeutic targets. We discuss current treatment approaches and the promising future of miRNAs as next-generation therapeutic agents for this condition. Full article

(This article belongs to the Section Small Non-Coding RNA)

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10 pages, 362 KiB

Open AccessReview

The Small Non-Coding RNA Profile of Human and Mouse Sperm

by Yoon Sing Yap, Pasquale Patrizio, Luisa Cimmino, Konstantinos Sdrimas and Aristeidis G. Telonis

Non-Coding RNA 2025, 11(1), 15; https://doi.org/10.3390/ncrna11010015 - 9 Feb 2025

Abstract

Small non-coding RNAs constitute a dynamic epigenetic layer in mature spermatozoa that can exert transgenerational regulatory functions. Here, we review recent advances in the field of small RNAs in spermatozoa, how their profiles change in response to lifestyle or environmental factors, and their [...] Read more.

Small non-coding RNAs constitute a dynamic epigenetic layer in mature spermatozoa that can exert transgenerational regulatory functions. Here, we review recent advances in the field of small RNAs in spermatozoa, how their profiles change in response to lifestyle or environmental factors, and their impact on offsprings’ physiology. The profile of these RNAs changes dramatically during spermatozoa maturation. The majority of intracellular small RNAs during early spermatogenesis are miRNAs and piRNAs, but, in mature spermatozoa, tRNA- and rRNA-derived fragments (tRFs and rRFs, respectively) are the predominant forms, primarily delivered from the epididymis via extracellular vesicles. Diet, exercise, and environmental exposures have a direct effect on small RNA levels in spermatozoa, and this differential abundance can reprogram the development of the embryo. Offsprings of fathers with different lifestyles can have different phenotypes, including altered metabolism or behavior. Therefore, small RNAs in spermatozoa are emerging as an important epigenetic layer in development and transgenerational inheritance. Full article

(This article belongs to the Section Small Non-Coding RNA)

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17 pages, 1920 KiB

Open AccessReview

The Role of microRNA in the Regulation of Differentiation and the Functionality of Osteoblasts, Osteoclasts, and Their Precursors in Osteoporosis

by Bulat I. Yalaev, Elena I. Kaletnik, Yulia S. Karpova, Zhanna E. Belaya, Ildar R. Minniakhmetov, Natalia G. Mokrysheva and Rita I. Khusainova

Non-Coding RNA 2025, 11(1), 14; https://doi.org/10.3390/ncrna11010014 - 8 Feb 2025

Abstract

Osteoporosis is a complex disease that is affected by a variety of factors, including genetic and epigenetic influences. While DNA markers for osteoporosis have been identified, they do not fully explain the hereditary basis of the disease. Epigenetic factors, such as small microRNAs [...] Read more.

Osteoporosis is a complex disease that is affected by a variety of factors, including genetic and epigenetic influences. While DNA markers for osteoporosis have been identified, they do not fully explain the hereditary basis of the disease. Epigenetic factors, such as small microRNAs (miRNAs), may provide a missing link in understanding the molecular mechanisms underlying osteoporosis. miRNAs are a class of non-coding RNAs that play a role in the epigenetic regulation of gene expression. They are known to be involved in various biological processes, including bone formation and remodelling. Differential expression of miRNAs has been linked to the pathological decrease in bone mineral density associated with osteoporosis. It has been shown that an abnormal miRNA expression pattern leads to a decrease in osteoblast activity and an increase in osteoclast activity. Further research into the role of miRNAs in osteoporosis may help to better understand this disease and identify potential therapeutic targets for treatment. Based on these assumptions, the study of miRNA expression patterns in osteoblasts, osteoclasts, and their precursors under normal and osteoporotic conditions is a rapidly growing field of scientific research. Although the results of this research are still incomplete and sometimes contradictory, they require additional scientific analysis to better understand the complex mechanisms involved. The purpose of this paper is to review the current research on miRNAs specifically expressed in osteoblasts and osteoclasts under both normal and pathological conditions. We will also discuss the potential applications of these miRNAs as biomarkers for osteoporosis diagnosis and as targets for osteoporosis treatment. Full article

(This article belongs to the Topic MicroRNA: Mechanisms of Action, Physio-Pathological Implications, and Disease Biomarkers, 3rd Edition)

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