Non-Coding RNA

20 pages, 1024 KiB

Open AccessReview

Partners in Silencing: Decoding the Mammalian Argonaute Interactome

by Srinaath Narasimhan and Stefan J. Erkeland

Non-Coding RNA 2025, 11(4), 62; https://doi.org/10.3390/ncrna11040062 - 19 Aug 2025

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MicroRNAs (miRNAs) are key post-transcriptional regulators controlling gene expression across several cellular processes, including development, proliferation, and apoptosis. Their biogenesis involves a multi-step pathway, including the processing of primary transcripts and the assembly of the RNA-Induced Silencing Complex (RISC) with Argonaute (AGO) proteins [...] Read more.

MicroRNAs (miRNAs) are key post-transcriptional regulators controlling gene expression across several cellular processes, including development, proliferation, and apoptosis. Their biogenesis involves a multi-step pathway, including the processing of primary transcripts and the assembly of the RNA-Induced Silencing Complex (RISC) with Argonaute (AGO) proteins at its core. This review provides a comprehensive overview of the molecular dynamics of miRNA-loaded RISC (miRISC), focusing on the post-translational modifications, the interactors of AGOs and the mechanisms that fine-tune and coordinate miRISC activity. The composition of miRISC influences AGO stability, localization, and silencing efficiency, thereby maintaining cellular homeostasis and development and mediating the response to various types of cellular stress. Uncommon regulatory mechanisms, including AGO modifications during, e.g., hypoxia or Type 2 T cell responses and miRISC functionality, with myriad RNA-binding proteins (RBPs), will be discussed. This review aims at highlighting the recent advances in the understanding of the intricate regulation of miRISC-driven gene silencing. Full article

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19 pages, 1628 KiB

Open AccessReview

The Role of Non-Coding RNAs in the Regulation of Oncogenic Pathways in Breast and Gynaecological Cancers

by Ammar Ansari, Aleksandra Szczesnowska, Natalia Haddad, Ahmed Elbediwy and Nadine Wehida

Non-Coding RNA 2025, 11(4), 61; https://doi.org/10.3390/ncrna11040061 - 6 Aug 2025

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Abstract

Female cancers such as breast and gynaecological cancers contribute to a significant global health burden and are a leading cause of fatality among women. With current treatment options often limited by resistance to cytotoxic drugs, side effects and lack of specificity to the [...] Read more.

Female cancers such as breast and gynaecological cancers contribute to a significant global health burden and are a leading cause of fatality among women. With current treatment options often limited by resistance to cytotoxic drugs, side effects and lack of specificity to the cancer, there is a pressing need for alternative treatments. Recent research has highlighted the promising role of non-coding RNAs (ncRNA) in regulating these issues and providing more targeted approaches to suppressing key cancer pathways. This review explores the involvement of the various types of non-coding RNAs in regulating key oncogenic pathways, namely, the MAPK, PI3K/Akt/mTOR, Wnt/β-catenin and p53 pathways, in a range of female cancers such as breast, cervical, ovarian and endometrial cancers. Evidence from a multitude of studies suggests that non-coding RNAs function as double-edged swords, serving as both oncogenes and tumour suppressors, depending on their expression and cellular interactions. By mapping and investigating these regulatory interactions, this review demonstrates the complexity and dual functionality of ncRNAs in cancer. Understanding these complex mechanisms is essential for the development of new and effective ncRNA-based diagnostic methods and targeted therapies in female cancer treatment. Full article

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18 pages, 1899 KiB

Open AccessArticle

MALAT1 Expression Is Deregulated in miR-34a Knockout Cell Lines

by Andrea Corsi, Tonia De Simone, Angela Valentino, Elisa Orlandi, Chiara Stefani, Cristina Patuzzo, Stefania Fochi, Maria Giusy Bruno, Elisabetta Trabetti, John Charles Rotondo, Chiara Mazziotta, Maria Teresa Valenti, Alessandra Ruggiero, Donato Zipeto, Cristina Bombieri and Maria Grazia Romanelli

Non-Coding RNA 2025, 11(4), 60; https://doi.org/10.3390/ncrna11040060 - 5 Aug 2025

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Abstract

Background/Objectives: Non-coding microRNA-34a (miR-34a) regulates the expression of key factors involved in several cellular processes, such as differentiation, apoptosis, proliferation, cell cycle, and senescence. Deregulation of the expression of these factors is implicated in the onset and progression of several human diseases, including [...] Read more.

Background/Objectives: Non-coding microRNA-34a (miR-34a) regulates the expression of key factors involved in several cellular processes, such as differentiation, apoptosis, proliferation, cell cycle, and senescence. Deregulation of the expression of these factors is implicated in the onset and progression of several human diseases, including cancer, neurodegenerative disorders, and pathologies associated with viral infections and inflammation. Despite numerous studies, the molecular mechanisms regulated by miR-34a remain to be fully understood. The present study aimed to generate miR-34a knockout cell lines to identify novel genes potentially regulated by its expression. Methods: We employed the CRISPR-Cas9 gene editing system to knock out the hsa-miR-34a gene in HeLa and 293T cell lines, two widely used models for studying molecular and cellular mechanisms. We compared proliferation rates and gene expression profiles via RNA-seq and qPCR analyses between the wild-type and miR-34a KO cell lines. Results: Knockout of miR-34a resulted in a decreased proliferation rate in both cell lines. Noteworthy, the ablation of miR-34a resulted in increased expression of the long non-coding RNA MALAT1. Additionally, miR-34a-5p silencing in the A375 melanoma cell line led to MALAT1 overexpression. Conclusions: Our findings support the role of the miR-34a/MALAT1 axis in regulating proliferation processes. Full article

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

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16 pages, 19172 KiB

Open AccessCommunication

DEAD-Box Helicase 3 Modulates the Non-Coding RNA Pool in Ribonucleoprotein Condensates During Stress Granule Formation

by Elizaveta Korunova, B. Celia Cui, Hao Ji, Aliaksandra Sikirzhytskaya, Srestha Samaddar, Mengqian Chen, Vitali Sikirzhytski and Michael Shtutman

Non-Coding RNA 2025, 11(4), 59; https://doi.org/10.3390/ncrna11040059 - 1 Aug 2025

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Abstract

Stress granule formation is a type of liquid–liquid phase separation in the cytoplasm, leading to RNA–protein condensates that are associated with various cellular stress responses and implicated in numerous pathologies, including cancer, neurodegeneration, inflammation, and cellular senescence. One of the key components of [...] Read more.

Stress granule formation is a type of liquid–liquid phase separation in the cytoplasm, leading to RNA–protein condensates that are associated with various cellular stress responses and implicated in numerous pathologies, including cancer, neurodegeneration, inflammation, and cellular senescence. One of the key components of mammalian stress granules is the DEAD-box RNA helicase DDX3, which unwinds RNA in an ATP-dependent manner. DDX3 is involved in multiple steps of RNA metabolism, facilitating gene transcription, splicing, and nuclear export and regulating cytoplasmic translation. In this study, we investigate the role of the RNA helicase DDX3’s enzymatic activity in shaping the RNA content of ribonucleoprotein (RNP) condensates formed during arsenite-induced stress by inhibiting DDX3 activity with RK-33, a small molecule previously shown to be effective in cancer clinical studies. Using the human osteosarcoma U2OS cell line, we purified the RNP granule fraction and performed RNA sequencing to assess changes in the RNA pool. Our results reveal that RK-33 treatment alters the composition of non-coding RNAs within the RNP granule fraction. We observed a DDX3-dependent increase in circular RNA (circRNA) content and alterations in the granule-associated intronic RNAs, suggesting a novel role for DDX3 in regulating the cytoplasmic redistribution of non-coding RNAs. Full article

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27 pages, 5245 KiB

Open AccessArticle

The Good, the Bad, or Both? Unveiling the Molecular Functions of LINC01133 in Tumors

by Leandro Teodoro Júnior and Mari Cleide Sogayar

Non-Coding RNA 2025, 11(4), 58; https://doi.org/10.3390/ncrna11040058 - 30 Jul 2025

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Abstract

Background/Objectives: Increasing evidence suggests that lncRNAs are core regulators in the field of tumor progression, with context-specific functions in oncogenic tumorigenesis. LINC01133, a lncRNA that has been identified as both an oncogene and a tumor suppressor, remains largely unexplored in terms of its [...] Read more.

Background/Objectives: Increasing evidence suggests that lncRNAs are core regulators in the field of tumor progression, with context-specific functions in oncogenic tumorigenesis. LINC01133, a lncRNA that has been identified as both an oncogene and a tumor suppressor, remains largely unexplored in terms of its molecular mechanisms. The purpose of this study was to conduct an in silico analysis, incorporating literature research on various cancer types, to investigate the structural and functional duality of LINC01133. This analysis aimed to identify pathways influenced by LINC01133 and evaluate its mechanism of action as a potential therapeutic target and diagnostic biomarker. Methods: In silico analyses and a narrative review of the literature were performed to predict conserved structural elements, functional internal loops, and overall conservation of the LINC01133 sequence among different vertebrate organisms, summarizing the empirical evidence regarding its roles as a tumor suppressor and tumor-promoting roles in various types of tumors. Results: LINC01133 harbors the evolutionarily conserved structural regions that might allow for binding to relevant driver signaling pathways, substantiating its specific functionality. Its action extends beyond classical tumor mechanisms, affecting proliferation, migration, invasion, and epigenetic pathways in various types of tumors, as indicated by the in silico results and narrative review of the literature we present here. Clinical outcome associations pointed to its potential as a biomarker. Conclusions: The dual character of LINC01133 in tumor biology further demonstrates its prospective therapeutic value, but complete elucidation of its mechanisms of action requires further investigation. This study establishes LINC01133 as a multifaceted lncRNA, supporting context-specific strategies in targeting its pathways, and calls for expanded research to harness its full potential in oncology. Full article

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

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2 pages, 137 KiB

Open AccessCorrection

Correction: Garmaa et al. A Systematic Review and Meta-Analysis of microRNA Profiling Studies in Chronic Kidney Diseases. Non-Coding RNA 2024, 10, 30

by Gantsetseg Garmaa, Stefania Bunduc, Tamás Kói, Péter Hegyi, Dezső Csupor, Dariimaa Ganbat, Fanni Dembrovszky, Fanni Adél Meznerics, Ailar Nasirzadeh, Cristina Barbagallo and Gábor Kökény

Non-Coding RNA 2025, 11(4), 57; https://doi.org/10.3390/ncrna11040057 - 30 Jul 2025

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Abstract

Text Correction [...] Full article

12 pages, 2351 KiB

Open AccessReview

circRNA/miRNA Networks Regulate KLF4 in Tumor Development

by Raffaele Frazzi, Enrico Farnetti and Davide Nicoli

Non-Coding RNA 2025, 11(4), 56; https://doi.org/10.3390/ncrna11040056 - 29 Jul 2025

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Abstract

Background/Objectives: Krüppel-like factor 4 (KLF4) emerged as an epigenetically regulated gene in a variety of settings, including cell reprogramming and malignant cell proliferation. The aim of the present manuscript is to explore the relationship described in recent years between circular [...] Read more.

Background/Objectives: Krüppel-like factor 4 (KLF4) emerged as an epigenetically regulated gene in a variety of settings, including cell reprogramming and malignant cell proliferation. The aim of the present manuscript is to explore the relationship described in recent years between circular RNAs, miRNAs, and KLF4. These have been shown to be involved in cancers having diverse histological origins, including some of the most prevalent and deadly tumors for the human population. Expression and protein levels of this transcription factor correlate with invasiveness and prognosis in a context- and tissue-specific fashion. Methods: The literature was obtained through two main PubMed queries. The first is “miRNA and KLF4 and cancer” and is limited to the last 5 years. The second is “circRNA and KLF4”, which yielded publications between 2013 and 2024. The oncological publications were selected. Results: A number of circRNA/miRNA axes that regulate the downstream transcription factor KLF4 emerged in the last few years. circRNAs act as sponges for miRNAs and synergize with KLF4, which can function as either a tumor promoter or suppressor in different tumors. Conclusions: The axes represented by circRNA/miRNA/KLF4 emerged as a new layer of epigenetic regulation. These RNA-based modulators explain the complex regulation of this transcription factor and open the way to new therapeutic targeting possibilities. Full article

(This article belongs to the Section Detection and Biomarkers of Non-Coding RNA)

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14 pages, 3198 KiB

Open AccessArticle

Small Nucleolar RNA from S. cerevisiae Binds to Phosphatidylinositol 4,5-Bisphosphate

by Irma A. Jiménez-Ramírez, Miguel A. Uc-Chuc, Luis Carlos Rodríguez Zapata and Enrique Castaño

Non-Coding RNA 2025, 11(4), 55; https://doi.org/10.3390/ncrna11040055 - 28 Jul 2025

Cited by 1 | Viewed by 303

Abstract

Background: snoRNAs have traditionally been known for their role as guides in post-transcriptional rRNA modifications. Previously, our research group identified several RNAs that may bind to PIP2 with LIPRNA-seq. Among them, snR191 stood out due to its potential specific interaction with this [...] Read more.

Background: snoRNAs have traditionally been known for their role as guides in post-transcriptional rRNA modifications. Previously, our research group identified several RNAs that may bind to PIP2 with LIPRNA-seq. Among them, snR191 stood out due to its potential specific interaction with this lipid, distinguishing itself from other snoRNAs. However, a detailed study is needed to define the molecular interactions between RNA and lipids, which remain unknown but may serve as a mechanism for transport or liquid–liquid phase separation. This study aimed to determine the interaction between a snoRNA called snR191 and PIP2. Method: A novel methodology for RNA-PIP2 interaction was carried out. Total RNA from Saccharomyces cerevisiae was incubated with PIP2-bound nitrocellulose membranes and RT-PCR reactions. We performed the prediction of snR191-PIP2 interaction by molecular docking and in silico mutations of snoR191. Results: From LIPRNA-seq analysis, we identified that PIP2-bound RNAs were significantly enriched in diverse biological processes, including transmembrane transport and redox functions. Our RNA-PIP2 interaction approach was successful. We demonstrated that snR191 specifically interacts with PIP2 in vitro. The elimination of DNA ensured that the interaction assay was RNA-specific, strengthening the robustness of the experiment. PIP2 was docked to snR191 in a stem–loop–stem motif. Six hydrogen bonds across four nucleotides mediated the PIP2-snR191 interaction. Finally, mutations in snR191 affected the structural folding. Conclusions: In this study, we demonstrate the effectiveness of a new methodology for determining RNA–lipid interactions, providing strong evidence for the specific interaction between snR191 and PIP2. Integrating biochemical and computational approaches has allowed us to understand the binding of these biomolecules. Therefore, this work significantly broadens our understanding of snR191-PIP2 interactions and opens new perspectives for further research. Full article

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

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19 pages, 1560 KiB

Open AccessArticle

Knockdown of the snoRNA-Jouvence Blocks the Proliferation and Leads to the Death of Human Primary Glioblastoma Cells

by Lola Jaque-Cabrera, Julia Buggiani, Jérôme Bignon, Patricia Daira, Nathalie Bernoud-Hubac and Jean-René Martin

Non-Coding RNA 2025, 11(4), 54; https://doi.org/10.3390/ncrna11040054 - 18 Jul 2025

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Abstract

Background/Objectives: Cancer research aims to understand the cellular and molecular mechanisms involved, in order to identify new therapeutic targets and provide patients with more effective therapies that generate fewer side undesirable and toxic effects. Previous studies have demonstrated the role of small [...] Read more.

Background/Objectives: Cancer research aims to understand the cellular and molecular mechanisms involved, in order to identify new therapeutic targets and provide patients with more effective therapies that generate fewer side undesirable and toxic effects. Previous studies have demonstrated the role of small nucleolar RNAs (snoRNAs) in many physiological and pathological cellular processes, including cancers. SnoRNAs are a group of non-coding RNAs involved in different post-transcriptional modifications of ribosomal RNAs. Recently, we identified a new snoRNA (jouvence), first in Drosophila, and thereafter, by homology, in humans. Methods: Here, we characterize the effect of the knockdown of jouvence by a sh-lentivirus on human primary patient-derived glioblastoma cells. Results: The sh-lentivirus anti-jouvence induces a significant decrease in cell proliferation and leads to cell death. EdU staining confirmed this decrease, while TUNEL also showed the presence of apoptotic cells. An RNA-Seq analysis revealed a decrease, in particular, in the level of BAALC, a gene known to potentiate the oncogenic ERK pathway and deregulating p21, leading to cell cycle blockage. Conclusions: Altogether, these results allow the hypothesis that the knockdown of jouvence could potentially be used as a new anti-cancer treatment (sno-Therapy), especially against glioblastoma and also, potentially, against acute myeloid leukemia (AML) due to the BAALC deregulation. Full article

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

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15 pages, 441 KiB

Open AccessFeature PaperReview

Direct circRNA-mRNA Binding Controls mRNA Fate: A New Mechanism for circRNAs

by Raffaele Garraffo and Manuel Beltran Nebot

Non-Coding RNA 2025, 11(4), 53; https://doi.org/10.3390/ncrna11040053 - 18 Jul 2025

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Abstract

Circular RNAs (circRNAs) are covalently closed RNA molecules generated through a non-canonical splicing event known as back-splicing. This particular class of non-coding RNAs has attracted growing interest due to its evolutionary conservation across eukaryotes, high expression in the central nervous system, and frequent [...] Read more.

Circular RNAs (circRNAs) are covalently closed RNA molecules generated through a non-canonical splicing event known as back-splicing. This particular class of non-coding RNAs has attracted growing interest due to its evolutionary conservation across eukaryotes, high expression in the central nervous system, and frequent dysregulation in various pathological conditions, including cancer. Traditionally, circRNAs have been characterised by their ability to function as microRNA (miRNA) and protein sponges. However, recent discoveries from multiple research groups have uncovered a novel and potentially transformative mechanism of action: the direct interaction of circRNAs with messenger RNAs (mRNAs) to regulate their fate. These interactions can influence mRNA stability and translation, revealing a new layer of post-transcriptional gene regulation. In this review, we present and analyse the latest evidence supporting the emerging role of circRNAs in diverse biological contexts. We highlight the growing body of research demonstrating circRNA-mRNA interactions as a functional regulatory mechanism and explore their involvement in key physiological and pathophysiological processes. Understanding this novel mechanism expands our knowledge of RNA-based regulation and opens new opportunities for therapeutic strategies targeting circRNA-mRNA networks in human disease. Full article

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26 pages, 5282 KiB

Open AccessArticle

Unraveling the Regulatory Impact of LncRNA Hnf1aos1 on Hepatic Homeostasis in Mice

by Beshoy Armanios, Jing Jin, Holly Kolmel, Ankit P. Laddha, Neha Mishra, Jose E. Manautou and Xiao-Bo Zhong

Non-Coding RNA 2025, 11(4), 52; https://doi.org/10.3390/ncrna11040052 - 4 Jul 2025

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Abstract

Background/Objectives: Long non-coding RNAs (lncRNAs) play significant roles in tissue development and disease progression and have emerged as crucial regulators of gene expression. The hepatocyte nuclear factor alpha antisense RNA 1 (HNF1A-AS1) lncRNA is a particularly intriguing regulatory molecule in liver biology that [...] Read more.

Background/Objectives: Long non-coding RNAs (lncRNAs) play significant roles in tissue development and disease progression and have emerged as crucial regulators of gene expression. The hepatocyte nuclear factor alpha antisense RNA 1 (HNF1A-AS1) lncRNA is a particularly intriguing regulatory molecule in liver biology that is involved in the regulation of cytochrome P450 enzymes via epigenetic mechanisms. Despite the growing recognition of lncRNAs in liver disease, the comprehensive role of HNF1A-AS1 in liver function remains unclear. This study aimed to investigate the roles of the mouse homolog of the human HNF1A-AS1 lncRNA HNF1A opposite strand 1 (Hnf1aos1) in liver function, gene expression, and cellular processes using a mouse model to identify potential therapeutic targets for liver disorders. Methods: The knockdown of Hnf1aos1 was performed in in vitro mouse liver cell lines using siRNA and in vivo livers of AAV-shRNA complexes. Changes in the global expression landscapes of mRNA and proteins were revealed using RNA-seq and proteomics, respectively. Changes in the selected genes were further validated via real-time quantitative polymerase chain reaction (RT-qPCR). Phenotypic changes were assessed via histological and absorbance-based assays. Results: After the knockdown of Hnf1aos1, RNA-seq and proteomics analysis revealed the differential gene expression of the mRNAs and proteins involved in the processes of molecular transport, liver regeneration, and immune signaling pathways. The downregulation of ABCA1 and SREBF1 indicates their role in cholesterol transport and fatty acid and triglyceride synthesis. Additionally, significant reductions in hepatic triglyceride levels were observed in the Hnf1aos1-knockdown group, underscoring the impact on lipid regulation. Notably, the knockdown of Hnf1aos1 also led to an almost complete depletion of CYP7A1, the rate-limiting enzyme in bile acid synthesis, highlighting its role in cholesterol homeostasis and hepatotoxicity. Histological assessments confirmed these molecular findings, with increased hepatic inflammation, hepatocyte swelling, and disrupted liver architecture observed in the Hnf1aos1-knockdown mice. Conclusions: This study illustrated that Hnf1aos1 is a critical regulator of liver health, influencing both lipid metabolism and immune pathways. It maintains hepatic lipid homeostasis, modulates lipid-induced inflammatory responses, and contributes to viral immunity, indirectly affecting glucose and lipid metabolic balance. Full article

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

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33 pages, 1562 KiB

Open AccessReview

Role of ncRNAs in the Development of Chronic Pain

by Mario García-Domínguez

Non-Coding RNA 2025, 11(4), 51; https://doi.org/10.3390/ncrna11040051 - 3 Jul 2025

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Abstract

Chronic pain is a multifactorial and complex condition that significantly affects individuals’ quality of life. The underlying mechanisms of chronic pain involve complex alterations in neural circuits, gene expression, and cellular signaling pathways. Recently, ncRNAs, such as miRNAs, lncRNAs, circRNAs, and siRNAs, have [...] Read more.

Chronic pain is a multifactorial and complex condition that significantly affects individuals’ quality of life. The underlying mechanisms of chronic pain involve complex alterations in neural circuits, gene expression, and cellular signaling pathways. Recently, ncRNAs, such as miRNAs, lncRNAs, circRNAs, and siRNAs, have been identified as crucial regulators in the pathophysiology of chronic pain. These ncRNAs modulate gene expression at both the transcriptional and post-transcriptional levels, affecting pain-related pathways like inflammation, neuronal plasticity, and sensory processing. miRNAs have been shown to control genes involved in pain perception and nociceptive signaling, while lncRNAs interact with chromatin remodeling factors and transcription factors to modify pain-related gene expression. CircRNAs act as sponges for miRNAs, thereby influencing pain mechanisms. siRNAs, recognized for their gene-silencing capabilities, also participate in regulating the expression of pain-related genes. This review examines the diverse roles of ncRNAs in chronic pain, emphasizing their potential as biomarkers for pain assessment and as targets for novel therapeutic strategies. A profound understanding of the ncRNA-mediated regulatory networks involved in chronic pain could result in more effective and personalized pain management solutions. Full article

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3 pages, 134 KiB

Open AccessCorrection

Correction: Piergentili et al. miR-125 in Breast Cancer Etiopathogenesis: An Emerging Role as a Biomarker in Differential Diagnosis, Regenerative Medicine, and the Challenges of Personalized Medicine. Non-Coding RNA 2024, 10, 16

by Roberto Piergentili, Enrico Marinelli, Gaspare Cucinella, Alessandra Lopez, Gabriele Napoletano, Giuseppe Gullo and Simona Zaami

Non-Coding RNA 2025, 11(4), 50; https://doi.org/10.3390/ncrna11040050 - 25 Jun 2025

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Abstract

There was an error in the original publication [...] Full article

25 pages, 1699 KiB

Open AccessArticle

LncRNA Subcellular Localization Across Diverse Cell Lines: An Exploration Using Deep Learning with Inexact q-mers

by Weijun Yi, Jason R. Miller, Gangqing Hu and Donald A. Adjeroh

Non-Coding RNA 2025, 11(4), 49; https://doi.org/10.3390/ncrna11040049 - 25 Jun 2025

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Abstract

Background: Long non-coding Ribonucleic Acids (lncRNAs) can be localized to different cellular compartments, such as the nuclear and the cytoplasmic regions. Their biological functions are influenced by the region of the cell where they are located. Compared to the vast number of lncRNAs, [...] Read more.

Background: Long non-coding Ribonucleic Acids (lncRNAs) can be localized to different cellular compartments, such as the nuclear and the cytoplasmic regions. Their biological functions are influenced by the region of the cell where they are located. Compared to the vast number of lncRNAs, only a relatively small proportion have annotations regarding their subcellular localization. It would be helpful if those few annotated lncRNAs could be leveraged to develop predictive models for localization of other lncRNAs. Methods: Conventional computational methods use q-mer profiles from lncRNA sequences and train machine learning models such as support vector machines and logistic regression with the profiles. These methods focus on the exact q-mer. Given possible sequence mutations and other uncertainties in genomic sequences and their role in biological function, a consideration of these variabilities might improve our ability to model lncRNAs and their localization. Thus, we build on inexact q-mers and use machine learning/deep learning techniques to study three specific problems in lncRNA subcellular localization, namely, prediction of lncRNA localization using inexact q-mers, the issue of whether lncRNA localization is cell-type-specific, and the notion of switching (lncRNA) genes. Results: We performed our analysis using data on lncRNA localization across 15 cell lines. Our results showed that using inexact q-mers (with q = 6) can improve the lncRNA localization prediction performance compared to using exact q-mers. Further, we showed that lncRNA localization, in general, is not cell-line-specific. We also identified a category of LncRNAs which switch cellular compartments between different cell lines (we call them switching lncRNAs). These switching lncRNAs complicate the problem of predicting lncRNA localization using machine learning models, showing that lncRNA localization is still a major challenge. Full article

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

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Non-Coding RNA, Volume 11, Issue 4 (August 2025) – 14 articles

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