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Background: Articular cartilage defects (ACD) are injuries with a diameter greater than 3 mm, resulting from wear and tear on joints. When the diameter of the defect exceeds 6 mm, it can further damage the surrounding joint cartilage, causing osteoarthritis (OA). Try to explain why OA is an irreversible disease, we hypothesize that damaged articular chondrocytes (DAC) may have reduced capacities to repair cartilage because its extracellular vesicle (EVs) that might directly contribute to OA formation., Methods: In this study, DAC-EVs and AC-EVs were isolated using ultracentrifugation. Next-generation sequencing was employed to screen for a pathogenic long non-coding RNA (lncRNA). After verifying its function in vitro, the corresponding small interfering RNA (siRNA) was constructed and loaded into extracellular vesicles, which were then injected into the knee joint cavities of rats., Results: The results revealed that DAC-EVs packaged lncRNA LOC102546541 acts as a competitive endogenous RNA (ceRNA) of MMP13, down-regulating miR-632. Consequently, the function of MMP13 in degrading the extracellular matrix is enhanced, promoting the development of osteoarthritis., Conclusions: This study uncovered a novel mode of OA pathogenesis using rat models, which DAC deliver pathogenic LOC102546541 packaged EVs to normal articular chondrocytes, amplifying the degradation of the extracellular matrix. Nonetheless, the functions of highly homologous human gene of LOC102546541 need to be verified in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Macrophage lipid accumulation is a critical contributor to foam cell formation and atherosclerosis. Tumor necrosis factor-α-induced protein 1 (TNFAIP1) is closely associated with cardiovascular disease. However, its role and molecular mechanisms in atherogenesis remain unclear. TNFAIP1 was knocked down in THP-1 macrophage-derived foam cells and apolipoprotein-deficient (apoE -/- ) mice using lentiviral vector. The expression of lncRNA enhancing endothelial nitric oxide synthase expression (LEENE), Forkhead box O1 (FoxO1) and ATP binding cassette transporter A1 (ABCA1) was evaluated by qRT-PCR and/or western blot. Lipid accumulation in macrophage was assessed by high-performance liquid chromatography and Oil red O staining. RNA immunoprecipitation and RNA pull-down assay were performed to verify the interaction between LEENE and FoxO1 protein. Atherosclerotic lesions were analyzed using HE, Oil red O and Masson staining. Our results showed that TNFAIP1 was significantly increased in THP-1 macrophages loaded with oxidized low-density lipoprotein. Knockdown of TNFAIP1 enhanced LEENE expression, promoted the direct interaction of LEENE with FoxO1 protein, stimulated FoxO1 protein degradation through the proteasome pathway, induced ABCA1 transcription, and finally suppressed lipid accumulation in THP-1 macrophage-derived foam cells. TNFAIP1 knockdown also up-regulated ABCA1 expression, improved plasma lipid profiles, enhanced the efficiency of reverse cholesterol transport and attenuated lesion area in apoE -/- mice. Taken together, these results provide the first direct evidence that TNFAIP1 aggravates atherosclerosis by promoting macrophage lipid accumulation via the LEENE/FoxO1/ABCA1 signaling pathway. TNFAIP1 may represent a promising therapeutic target for atherosclerotic cardiovascular disease., (© 2024. The Author(s) under exclusive licence to University of Navarra.)

The long non-coding RNA (lncRNA) Small Nucleolar RNA Host Gene 4 (SNHG4) has been demonstrated to be significantly downregulated in various inflammatory conditions, yet its role in chronic obstructive pulmonary disease (COPD) remains elusive. This study aims to elucidate the biological function of SNHG4 in COPD and to unveil its potential molecular targets. Our findings reveal that both SNHG4 and Four and a Half LIM Domains 1 (FHL1) were markedly downregulated in COPD, whereas microRNA-409-3p (miR-409-3p) was upregulated. Importantly, SNHG4 exhibited a negative correlation with inflammatory markers in patients with COPD, but a positive correlation with forced expiratory volume in 1s percentage (FEV1%). SNHG4 distinguished COPD patients from non-smokers with high sensitivity, specificity, and accuracy. Overexpression of SNHG4 ameliorated cigarette smoke extract (CSE)-mediated inflammation, apoptosis, oxidative stress, and airway remodeling in 16HBE bronchial epithelial cells. These beneficial effects of SNHG4 overexpression were reversed by the overexpression of miR-409-3p or the silencing of FHL1. Mechanistically, SNHG4 competitively bound to miR-409-3p, mediating the expression of FHL1, and consequently improving inflammation, apoptosis, oxidative stress, and airway remodeling in 16HBE cells. Additionally, SNHG4 regulated the miR-409-3p/FHL1 axis to inhibit the activation of the mitogen-activated protein kinase (MAPK) pathway induced by CSE. In a murine model of COPD, knockdown of SNHG4 exacerbated CSE-induced pulmonary inflammation, apoptosis, and oxidative stress. In summary, our data affirm that SNHG4 mitigates pulmonary inflammation, apoptosis, and oxidative damage mediated by COPD through the regulation of the miR-409-3p/FHL1 axis., (© 2024. The Author(s).)

Although bone marrow mesenchymal stem cells (BM-MSCs)-derived exosomes have been reported to be closely associated with acute myeloid leukemia (AML) progression and chemo-resistance, but its detailed functions and molecular mechanisms have not been fully delineated. Besides, serum RNA m6A demethylase fat mass and obesity-associated protein (FTO)-containing exosomes are deemed as important indicators for cancer progression, and this study aimed to investigate the role of BM-MSCs-derived FTO-exosomes in regulating the malignant phenotypes of AML cells. Here, we verified that BM-MSCs-derived exosomes delivered FTO to promote cancer aggressiveness, stem cell properties and Cytosine arabinoside (Ara-C)-chemoresistance in AML cells, and the underlying mechanisms were also uncovered. Our data suggested that BM-MSCs-derived FTO-exo demethylated m6A modifications in the m6A-modified LncRNA GLCC1 to facilitate its combination with the RNA-binding protein Hu antigen R (HuR), which further increased the stability and expression levels of LncRNA GLCC1. In addition, LncRNA GLCC1 was verified as an oncogene to facilitate cell proliferation and enhanced Ara-C-chemoresistance in AML cells. Further experiments confirmed that demethylated LncRNA GLCC1 served as scaffold to facilitate the formation of the IGF2 mRNA binding protein 1 (IGF2BP1)-c-Myc complex, which led to the activation of the downstream tumor-promoting c-Myc-associated signal pathways. Moreover, our rescuing experiments validated that the promoting effects of BM-MSCs-derived FTO-exo on cancer aggressiveness and drug resistance in AML cells were abrogated by silencing LncRNA GLCC1 and c-Myc. Thus, the present firstly investigated the functions and underlying mechanisms by which BM-MSCs-derived FTO-exo enhanced cancer aggressiveness and chemo-resistance in AML by modulating the LncRNA GLCC1-IGF2BP1-c-Myc signal pathway, and our work provided novel biomarkers for the diagnosis, treatment and therapy of AML in clinic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Key Message: Sl-lncRNA20718 acts as an eTM of Sl-miR6022 regulating its expression thereby affecting SlRLP6/10 expression. SlRLP6/10 regulate PRs expression, ROS accumulation, and JA/ET content thereby affecting tomato resistance to P. infestans. Tomato (Solanum lycopersicum) is an important horticultural and cash crop whose yield and quality can be severely affected by Phytophthora infestans (P. infestans). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are widely involved in plant defense responses against pathogens. The involvement of Sl-lncRNA20718 and Sl-miR6022 in tomato resistance to P. infestans as well as the targeting of Sl-miR6022 to receptor-like protein genes (RLPs) were predicted in our previous study. However, uncertainty exists regarding their potential interaction as well as the molecular processes regulating tomato resistance. Here, we found that Sl-lncRNA20718 and Sl-miR6022 are positive and negative regulators of tomato resistance to P. infestans by gain- and loss-of-function experiments, respectively. Overexpression of Sl-lncRNA20718 decreased the expression of Sl-miR6022, induced the expression of PRs, reduced the diameter of lesions (DOLs), thereby enhanced disease resistance. A six-point mutation in the binding region of Sl-lncRNA20718 to Sl-miR6022 disabled the interaction, indicating that Sl-lncRNA20718 acts as an endogenous target mimic (eTM) of Sl-miR6022. We demonstrated that Sl-miR6022 cleaves SlRLP6/10. Overexpression of Sl-miR6022 decreases the expression levels of SlRLP6/10, induces the accumulation of reactive oxygen species (ROS) and reduces the content of JA and ET, thus inhibiting tomato resistance to P. infestans. In conclusion, our study provides detailed information on the lncRNA20718-miR6022-RLPs module regulating tomato resistance to P. infestans by affecting the expression of disease resistance-related genes, the accumulation of ROS and the phytohormone levels, providing a new reference for tomato disease resistance breeding., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rotator cuff tear (RCT) is a common shoulder disorder related to pain and dysfunction. However, the pathological mechanism of RCT remains unclear. Thus, this study aims to investigate the molecular events in RCT synovium and identify possible target genes and pathways as determined by RNA sequencing (RNA-Seq). The synovial tissue was biopsied from 3 patients with RCT (RCT group) and 3 patients with shoulder instability (Control group) during arthroscopic surgery. Then, differentially expressed (DE) mRNAs, long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs) were comprehensively profiled by RNA-Seq. Gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and competing endogenous RNA (ceRNA) network analysis were performed to identify the potential functions of these DE genes. 447 mRNAs, 103 lncRNAs and 15 miRNAs were identified differentially expressed. The DE mRNAs were highlighted in inflammatory pathway including up-regulated T cell costimulation, positive regulation of T cell activation, and T cell receptor signaling. Down-regulated fatty acid degradation pathway and 5'-AMP-activated protein kinase (AMPK) signaling in RCT group are also enriched. Validation assay showed that the expression of pro-inflammatory molecules including IL21R, CCR5, TNFSF11, and MMP11 was significantly increased in RCT group compared with Control group. CeRNA analysis further revealed lncRNA-miRNA-mRNA regulatory networks involving IL21R and TNFSF11 in RCT. Activated synovial inflammation is the remarkable event of RCT. Importantly, increased T cell activation and disordered fatty acid metabolism signaling might play a significant role. ceRNA networks involving IL21R and TNFSF11 identified could potentially control the progression of RCT. In conclusion, our findings could provide new evidence for the molecular mechanisms of RCT and might identify new therapeutic targets., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The Kazakh horse, renowned for its excellence as a breed, exhibits distinctive reproductive traits characterized by early maturity and seasonal estrus. While normal reproductive function is crucial for ensuring the breeding and expansion of the Kazakh horse population, a noteworthy decline in reproductive capabilities is observed after reaching 14 years of age., Methods: In this study, ovarian granulosa cells (GCs) were meticulously collected from Kazakh horses aged 1, 2, 7, and above 15 years old (excluding 15 years old) for whole transcriptome sequencing., Results: The analysis identified and selected differentially expressed mRNAs, lncRNAs, miRNAs, and circRNAs for each age group, followed by a thorough examination through GO enrichment analysis. The study uncovered significant variations in the expression profiles of mRNAs, lncRNAs, miRNAs, and circRNAs within GCs at different stages of maturity. Notably, eca-miR-486-3p and miR-486-y exhibited the highest degree of connectivity. Subsequent GO, KEGG, PPI, and ceRNA network analyses elucidated that the differentially expressed target genes actively participate in signaling pathways associated with cell proliferation, apoptosis, and hormonal regulation. These pathways include but are not limited to the MAPK signaling pathway, Hippo signaling pathway, Wnt signaling pathway, Calcium signaling pathway, Aldosterone synthesis and secretion, Cellular senescence, and NF-kappa B signaling pathway-essentially encompassing signal transduction pathways crucial to reproductive processes., Discussion: This research significantly contributes to unraveling the molecular mechanisms governing follicular development in Kazakh horses. It establishes and preliminarily validates a differential regulatory network involving lncRNA-miRNA-mRNA, intricately associated with processes such as cell proliferation, differentiation, and apoptosis and integral to the developmental intricacies of stromal follicles. The findings of this study provide a solid theoretical foundation for delving deeper into the realm of reproductive aging in Kazakh mares, presenting itself as a pivotal regulatory pathway in the context of horse ovarian development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ren, Wang, Zeng, Wang, Meng and Yao.)

Disulfidptosis, a novel type of programmed cell death, has attracted researchers' attention worldwide. However, the role of disulfidptosis-related lncRNAs (DRLs) in liver hepatocellular carcinoma (LIHC) not yet been studied. We aimed to establish and validate a prognostic signature of DRLs and analyze tumor microenvironment (TME) and drug susceptibility in LIHC patients. RNA sequencing data, mutation data, and clinical data were obtained from the Cancer Genome Atlas Database (TCGA). Lasso algorithm and cox regression analysis were performed to identify a prognostic DRLs signature. Kaplan-Meier curves, principal component analysis (PCA), nomogram and calibration curve, function enrichment, TME, immune dysfunction and exclusion (TIDE), tumor mutation burden (TMB), and drug sensitivity analyses were analyzed. External datasets were used to validate the predictive value of DRLs. qRT-PCR was also used to validate the differential expression of the target lncRNAs in tissue samples and cell lines. We established a prognostic signature for the DRLs (MKLN1-AS and TMCC1-AS1) in LIHC. The signature could divide the LIHC patients into low- and high-risk groups, with the high-risk subgroup associated with a worse prognosis. We observed discrepancies in tumor-infiltrating immune cells, immune function, function enrichment, and TIDE between two risk groups. LIHC patients in the high-risk group were more sensitive to several chemotherapeutic drugs. External datasets, clinical tissue, and cell lines confirmed the expression of MKLN1-AS and TMCC1-AS1 were upregulated in LIHC and associated with a worse prognosis. The novel signature based on the two DRLs provide new insight into LIHC prognostic prediction, TME, and potential therapeutic strategies., (© 2024. The Author(s).)

Hydroquinone (HQ), one of the main active metabolites of benzene, can induce the abnormal expression of long non-coding RNA (lncRNA). Studies have shown that lncRNA plays an important role in the occurrence of hematologic tumors induced by benzene or HQ. However, the molecular mechanism remains to be elucidated. Here, we investigated the molecular mechanism by which poly(ADP-ribose)polymerase 1 (PARP-1) interacts with DNA methyltransferase 1 (DNMT1) to regulate promoter methylation mediated linc01132 expression in HQ-induced TK6 malignant transformed cells (HQ-MT). The results revealed that the expression of linc01132 was increased in benzene-exposed workers and HQ-MT cells. The methylation of linc01132 promoter region was inhibited. Furthermore, in HQ-MT cells treated with 5-Aza-2'-deoxycytidine (5-AzaC) (DNA methyltransferase inhibitor) or trichostatin A (TSA) (histone deacetylation inhibitor), the expression of linc01132 was increased due to the regulation of DNA promoter methylation level by inhibiting DNMT1 expression. The methylation level of linc01132 promoter was correlated negatively with the expression of linc01132 in benzene-exposed workers, indicating that DNA methylation may contribute the expression of linc01132. Knockout of DNMT1, not DNMT3b, increased the expression of linc01132 as well as the demethylation of linc01132 promoter in HQ-MT cells. It was found that by knockdown PARP-1, the expression of DNMT1 in the nucleus was increased by immunofluorescence confocal microscopy, leading to the inhibition of hypermethylation in the promoter region of linc01132. Therefore, PARP-1 inhibits DNA methyltransferase (DNMT)-mediated promoter methylation and plays a role in linc01132 expression in benzene-exposed workers or HQ-MT cells, and is associated with benzene or HQ induced leukemia progression.

Platinum-taxane chemotherapy is the first-line standard-of-care treatment administered to patients with epithelial ovarian cancer (EOC), and faces the major challenge of cisplatin resistance. Aurora Kinase A (AURKA) is a serine/threonine kinase, acting as an oncogene by participating in microtubule formation and stabilization. In this study, we demonstrate that AURKA binds with DDX5 directly to form a transcriptional coactivator complex to induce the transcription and upregulation of an oncogenic long non-coding RNA, TMEM147-AS1, which sponges hsa-let-7b/7c-5p leading to the increasing expression of AURKA as a feedback loop. The feedback loop maintains EOC cisplatin resistance via activation of lipophagy. These findings underscore the feedback loop of AURKA/DDX5/TMEM147-AS1/let-7 provides mechanistic insights into the combined use of TMEM147-AS1 siRNA and VX-680, which can help improve EOC cisplatin treatment. Our mathematical model shows that the feedback loop has the potential to act as a biological switch to maintain on- (activated) or off- (deactivated) status, implying the possible resistance of single use of VX-680 or TMEM147-AS1 siRNA. The combined use reduces both the protein level of AURKA using TMEM147-AS1 siRNA and its kinase activity using VX-680, showing more significant effect than the use of TMEM147-AS1 siRNA or VX-680 alone, which provides a potential strategy for EOC treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Osteoarthritis (OA) is one of the most common forms of degenerative arthritis and a major cause of pain and disability. Ferroptosis, a novel mode of cell death, has been verified to participate in the development of OA, but its mechanism is still unclear. This paper analyzed the ferroptosis-related genes (FRGs) in OA and explored their potential clinical value., Methods: We downloaded data through the GEO database and screened for DEGs. Subsequently, FRGs were obtained using two machine learning methods, LASSO regression and SVM-RFE. The accuracy of the FRGs as disease diagnosis was identified using ROC curves and externally validated. The CIBERSORT analyzed the immune microenvironment rug regulatory network constructed through the DGIdb. The competitive endogenous RNA (ceRNA) visualization network was constructed to search for possible therapeutic targets. The expression levels of FRGs were verified by qRT-PCR and immunohistochemistry., Results: In this study, we found 4 FRGs. The ROC curve showed that the combined 4 FRGs had the highest diagnostic value. Functional enrichment analysis showed that the 4 FRGs in OA could influence the development of OA through biological oxidative stress, immune response, and other processes. qRT-PCR and immunohistochemistry verified the expression of these key genes, further confirming our findings. Monocytes and macrophages are heavily infiltrated in OA tissues, and the persistent state of immune activation may promote the progression of OA. ETHINYL ESTRADIOL was a possible targeted therapeutic agent for OA. Meanwhile, ceRNA network analysis identified some lncRNAs that could regulate the FRGs., Conclusion: We identify 4 FRGs (AQP8, BRD7, IFNA4, and ARHGEF26-AS1) closely associated with bio-oxidative stress and immune response, which may become early diagnostic and therapeutic targets for OA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Qiu, Yao, Li, Xiao, Meng, Huang, Cai, Wen, Huang, Zhu, Chen, Long and Li.)

In recent years, breakthroughs in bioinformatics have been made with the discovery of many functionally significant non-coding RNAs (ncRNAs). The discovery of these ncRNAs has further demonstrated the multi-level characteristics of intracellular gene expression regulation, which plays an important role in assisting diagnosis, guiding clinical drug use and determining prognosis in the treatment process of various diseases. microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are the three major types of ncRNAs that interact with each other. Studies have shown that lncRNAs and circRNAs can sponge miRNAs, thereby influencing normal physiological processes and regulating mRNA expression and, thus, the physiological state of cells. This paper summarizes the mechanism of action and research progress of the three ncRNA and seven types of modalities. This summary is intended to provide new ideas for diagnosing and treating diseases and researching and developing new drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Long non-coding RNAs (lncRNAs) are important regulators of biological processes. It has recently been shown that some lncRNAs include small open reading frames (sORFs) that can encode small peptides of no more than 100 amino acids. However, existing methods are commonly applied to human and animal datasets and still suffer from low feature representation capability. Thus, accurate and credible prediction of sORFs with coding ability in plant lncRNAs is imperative. This paper proposes a new method termed sORFPred, in which we design a model named MCSEN by combining multi-scale convolution and Squeeze-and-Excitation Networks to fully mine distinct information embedded in sORFs, integrate and optimize multiple sequence-based and physicochemical feature descriptors, and built a two-layer prediction classifier based on Bayesian optimization algorithm and Extra Trees. sORFPred has been evaluated on sORFs datasets of three species and experimentally validated sORFs dataset. Results indicate that sORFPred outperforms existing methods and achieves 97.28% accuracy, 97.06% precision, 97.52% recall, and 97.29% F1-score on Arabidopsis thaliana, which shows a significant improvement in prediction performance compared to various conventional shallow machine learning and deep learning models., (© 2023. International Association of Scientists in the Interdisciplinary Areas.)

Recently, small open reading frames (sORFs) in long noncoding RNA (lncRNA) have been demonstrated to encode small peptides that can help study the mechanisms of growth and development in organisms. Since machine learning-based computational methods are less costly compared with biological experiments, they can be used to identify sORFs and provide a basis for biological experiments. However, few computational methods and data resources have been exploited for identifying sORFs in plant lncRNA. Besides, machine learning models produce underperforming classifiers when faced with a class-imbalance problem. In this study, an alternative method called SMOTE based on weighted cosine distance (WCDSMOTE) which enables interaction with feature selection is put forward to synthesize minority class samples and weighted edited nearest neighbor (WENN) is applied to clean up majority class samples, thus, hybrid sampling WCDSMOTE-ENN is proposed to deal with imbalanced datasets with the multi-angle feature. A heterogeneous classifier ensemble is introduced to complete the classification task. Therefore, a novel computational method that is based on class-imbalance learning to identify the sORFs with coding potential in plant lncRNA (sORFplnc) is presented. Experimental results manifest that sORFplnc outperforms existing computational methods in identifying sORFs with coding potential. We anticipate that the proposed work can be a reference for relevant research and contribute to agriculture and biomedicine., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

As the most pervasive epigenetic mark present on mRNA and lncRNA, N6-methyladenosine (m6A) RNA methylation regulates all stages of RNA life in various biological processes and disease mechanisms. Computational methods for deciphering RNA modification have achieved great success in recent years; nevertheless, their potential remains underexploited. One reason for this is that existing models usually consider only the sequence of transcripts, ignoring the various regions (or geography) of transcripts such as 3'UTR and intron, where the epigenetic mark forms and functions. Here, we developed three simple yet powerful encoding schemes for transcripts to capture the submolecular geographic information of RNA, which is largely independent from sequences. We show that m6A prediction models based on geographic information alone can achieve comparable performances to classic sequence-based methods. Importantly, geographic information substantially enhances the accuracy of sequence-based models, enables isoform- and tissue-specific prediction of m6A sites, and improves m6A signal detection from direct RNA sequencing data. The geographic encoding schemes we developed have exhibited strong interpretability, and are applicable to not only m6A but also N1-methyladenosine (m1A), and can serve as a general and effective complement to the widely used sequence encoding schemes in deep learning applications concerning RNA transcripts., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The yield and quality of tomatoes (Solanum lycopersicum) is seriously affected by Phytophthora infestans. The long non-coding RNA (lncRNA) Sl-lncRNA39896 is induced after P. infestans infection and was previously predicted to act as an endogenous target mimic (eTM) for the microRNA Sl-miR166b, which function in stress responses. Here, we further examined the role of Sl-lncRNA39896 and Sl-miR166b in tomato resistance to P. infestans. Sl-miR166b levels were higher in Sl-lncRNA39896-knockout mutants than in wild-type plants, and the mutants displayed enhanced resistance to P. infestans. A six-point mutation in the region of Sl-lncRNA39896 that binds to Sl-miR166b disabled the interaction, suggesting that Sl-lncRNA39896 acts as an eTM for Sl-miR166b. Overexpressing Sl-miR166b yielded a similar phenotype to that produced by Sl-lncRNA39896-knockout, whereas silencing of Sl-miR166b impaired resistance. We verified that Sl-miR166b cleaved transcripts of its target class III homeodomain-leucine zipper genes SlHDZ34 and SlHDZ45. Silencing of SlHDZ34/45 decreased pathogen accumulation in plants infected with P. infestans. Additionally, jasmonic acid and ethylene contents were elevated following infection in the plants with enhanced resistance. Sl-lncRNA39896 is the first known lncRNA to negatively regulate resistance to P. infestans in tomato. We propose a novel mechanism in which the lncRNA39896-miR166b-HDZ module modulates resistance to P. infestans., (© 2022 Institute of Botany, Chinese Academy of Sciences.)

Mammalian follicle development is a complex biological process regulated by several factors. More than 99% of the follicles in goat ovaries will be atresia and only a few will eventually mature and ovulate. To investigate the potential long non-coding RNAs (lncRNAs) that regulate the expression of genes associated with follicular dominance or atresia, RNA-seq was performed on dominant follicles (DFs) and subordinate follicles (SFs) of granulosa cells from goats at the first follicular wave. A total of 92 differentially expressed lncRNAs and 676 differentially expressed mRNAs were detected in both types of follicles. The qRT-PCR results were consistent with the transcriptome sequencing data. Kyoto Encyclopedia of Genes and Genomes analysis of the differentially expressed mRNAs revealed that LHR and LDLR are associated with follicle dominance and are involved in the ovarian steroidogenesis pathway. The co-located mRNAs CALM2 and PPP1CA were significantly enriched during oocyte meiosis and in the cAMP and oxytocin signalling pathways. The co-expressed mRNAs were significantly enriched in the oestrogen signalling pathway and in ovarian steroidogenesis and progesterone-mediated oocyte maturation. A co-expression network of lncRNAs, target genes and differentially expressed genes was constructed. Follicle development-related genes, such as LDLR, NOTCH1 and FGF12, were included. These findings expand the lncRNA catalogue and provide a basis for further studies on the mechanism of regulating follicular development in goats., (© 2022 Wiley-VCH GmbH.)

Long non-coding RNA (lncRNA) contains short open reading frames (sORFs), and sORFs-encoded short peptides (SEPs) have become the focus of scientific studies due to their crucial role in life activities. The identification of SEPs is vital to further understanding their regulatory function. Bioinformatics methods can quickly identify SEPs to provide credible candidate sequences for verifying SEPs by biological experimenrts. However, there is a lack of methods for identifying SEPs directly. In this study, a machine learning method to identify SEPs of plant lncRNA (ISPL) is proposed. Hybrid features including sequence features and physicochemical features are extracted manually or adaptively to construct different modal features. In order to keep the stability of feature selection, the non-linear correction applied in Max-Relevance-Max-Distance (nocRD) feature selection method is proposed, which integrates multiple feature ranking results and uses the iterative random forest for different modal features dimensionality reduction. Classification models with different modal features are constructed, and their outputs are combined for ensemble classification. The experimental results show that the accuracy of ISPL is 89.86% percent on the independent test set, which will have important implications for further studies of functional genomic.

The redox homeostasis system regulates many biological processes, intracellular antioxidant production and redox signaling. However, long noncoding RNAs (lncRNAs) involved in redox regulation have rarely been reported. Herein, we reported that downregulation of MAGI2-AS3 decreased the superoxide level in Human fibroblasts (Fbs), a replicative aging model, as detected by the fluorescent probes dihydroethidium (DHE) and MitoSOX™ Red. RNA pulldown combined with mass spectrometry showed that HSPA8 is a novel interacting protein of MAGI2-AS3, which was further confirmed by photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP). Downregulation of MAGI2-AS3 decreased the hydrogen peroxide (H 2 O 2 ) content by stabilizing the HSPA8 protein level via inhibiting the protesome degradation of HSPA8. Further evidence showed that MAGI2-AS3 interacted with the C-terminal domain (CTD) of HSPA8. Downregulation of MAGI2-AS3 delayed cell senescence, while this antiaging effect was abolished by HSPA8 knockdown. The underlying molecular mechanism by which MAGI2-AS3 knockdown inhibited cell senescence was mediated via suppression of the ROS/MAP2K6/p38 signaling pathway. Taken together, these findings revealed that downregulation of lncRNA MAGI2-AS3 decreased the H 2 O 2 content and delayed cell senescence by stabilizing the HSPA8 protein level, identifying a potential antiaging application., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

This study researched the function of long non-coding RNA LINC00365 in lung adenocarcinoma (LAD) progression. LINC00365, miR-429, and KCTD12 expression in the LAD clinical tissues and cells were detcetd by qRT-PCR and Western blot. LINC00365, miR-429, and KCTD12 effects on H1975 cells malignant phenotype were detected by cell counting kit-8 assay, clone formation experiment, Transwell experiment, and glycolysis. Dual luciferase reporter gene assay and RNA pull-down assay were implemented. LINC00365 effect on H1975 cells in vivo growth was detected. LINC00365 was low expressed in the LAD patients and cells, associating with poor outcome. LINC00365 up-regulation attenuated H1975 cells proliferation, migration, invasion, glycolysis and in vivo growth. LINC00365 inhibited KCTD12 expression by sponging miR-429. miR-429 up-regulation and KCTD12 down-regulation partial reversed LINC00365 inhibition on H1975 cells malignant phenotype. Thus, LINC00365 inhibited LAD progression and glycolysis via targeting miR-429/KCTD12 axis. LINC00365 might be a potential candidate for LAD target treatment clinically., (© 2022 Wiley Periodicals LLC.)

Both inflammatory response and oxidative stress are regarded as two critical contributors to atherosclerosis. Kcnq1 overlapping transcript 1 (KCNQ1OT1) is an imprinted antisense long non-coding RNA in the kcnq1 locus. Our previous study has demonstrated that KCNQ1OT1 aggravates atherosclerosis by promoting macrophage lipid accumulation. However, its role in atherogenesis remains to be elucidated. This study aimed to observe the impact of KCNQ1OT1 on oxidized low-density lipoprotein (ox-LDL)-induced inflammatory response and oxidative stress and to explore the underlying mechanism. We found that ox-LDL up-regulated KCNQ1OT1 expression in THP-1 macrophages. Knockdown of KCNQ1OT1 increased miR-137 levels, decreased tumor necrosis factor-α-induced protein 1 (TNFAIP1) expression, and inhibited inflammatory response and alleviated oxidative stress in ox-LDL-treated THP-1 macrophages. A ceRNA regulatory network was identified among KCNQ1OT1, miR-137 and TNFAIP1. The inhibitory effect of KCNQ1OT1 knockdown on inflammatory response and oxidative stress was significantly reversed by miR-137 prevention or TNFAIP1 overexpression. In summary, these findings suggest that silencing of KCNQ1OT1 suppresses inflammatory response and oxidative stress induced by ox-LDL through the miR-137/TNFAIP1 pathway in THP-1 macrophages, thereby providing novel mechanistical insights into its pro-atherosclerotic action., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The long non-coding RNA (lncRNA) taurine up-regulated gene 1 (TUG1) acts as tumor-promoting factor in colorectal cancer (CRC). We aimed to elucidate the mechanism by which the transcription factor specificity protein 1 (SP1) regulates TUG1 and microRNAs (miRs)/mRNAs in the context of CRC, which has not been fully studied before. Expression patterns of TUG1 and SP1 were determined in clinical CRC samples and cells, followed by identification of their interaction. Next, the functional significance of TUG1 in CRC was investigated. An in vivo CRC model was established to validate the effect of TUG1. The results demonstrated that TUG1 and SP1 were highly-expressed in CRC, wherein SP1 bound to the TUG1 promoter and consequently, positively regulated its expression. Silencing of TUG1 caused suppression of CRC cell growth and promotion of cell apoptosis. TUG1 could bind to miR-421 to increase KDM2A expression, a target gene of miR-421. TUG1 could activate the ERK pathway by impairing miR-421-targeted inhibition of KDM2A. Additionally, SP1 could facilitate the tumorigenesis of CRC cells in vivo by regulating the TUG1/miR-421/KDM2A/ERK axis. Altogether, the current study emphasizes the oncogenic role of TUG1 in CRC, and illustrates its interactions with the upstream transcription factor SP1 and the downstream modulatory axis miR-421/KDM2A/ERK, thus offering novel insights into the cancerogenic mechanism in CRC., (© 2022. The Author(s).)

The long non-coding RNA GAS5 (GAS5) is reportedly implicated in glaucoma. However, its significance in human trabecular meshwork cells (HTMCs) remains largely unclear. Here, we investigated the effect of GAS5 on the function of HTMCs and its interaction with miR-29b-3p in HTMCs. We established an H 2 O 2 -induced oxidative injury model using HTMCs. RT-qPCR or western blotting was performed to examine the expression of the indicated genes. Luciferase reporter assay was used to determine the interaction between GAS5, miR-29b-3p, miR-29b-3p, and STAT3. CCK8 assay was used to assess the proliferative rate of HTMCs. Exposure to H 2 O 2 increased the expression of Bax, cleaved caspase-3, and extracellular matrix (ECM) proteins, accompanied by reduced Bcl-2 expression. These H 2 O 2 -induced changes were effectively alleviated by GAS5 knockdown with sh-GAS5. MiR-29b-3p was directly regulated by GAS5. The effect of sh-GAS5 on ECM protein expression was also observed with the miR-29b-3p mimic. STAT3 was directly regulated by miR-29b-3p. MiR-29b-3p silencing alleviated STAT3 inhibition, followed by the restoration of cell vitality, Bax, Bcl-2, and cleaved caspase-3 expression, and ECM deposition. Our study is the first experimental investigation to shed light on a novel molecular mechanism of the GAS5/miR-29b-3p/STAT3 axis in an H 2 O 2 -induced oxidative injury model using HTMCs, which may offer a promising therapeutic approach against glaucoma., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Long non-coding RNA (lncRNA), which is a type of non-coding RNA, was reported to contain short open reading frames (sORFs). SORFs-encoded short peptides (SEPs) have been demonstrated to play a crucial role in regulating the biological processes such as growth, development, and resistance response. The identification of SEPs is vital to further understanding their function. However, there is still a lack of methods for identifying SEPs effectively and rapidly. In this study, a novel method for lncRNA-encoded short peptides identification based on feature subset recombination and ensemble learning, lncPepid, is developed. lncPepid transforms the data of Zea mays and Arabidopsis thaliana into hybrid features from two aspects including sequence composition and physicochemical properties separately. It optimizes hybrid features by proposing a novel weighted iteration-based feature selection method to recombine a stable subset that characterizes SEPs effectively. Different classification models with different optimized features are constructed and tested separately. The outputs of the optimal models are integrated for ensemble classification to improve efficiency. Experimental results manifest that the geometric mean of sensitivity and specificity of lncPepid is about 70% on the identification of functional SEPs derived from multiple species. It is an effective and rapid method for the identification of lncRNA-encoded short peptides. This study can be extended to the research on SEPs from other species and have crucial implications for further findings and studies of functional genomics., (© 2021. International Association of Scientists in the Interdisciplinary Areas.)

The interactions between microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play important roles in biological activities. Specially, lncRNAs as endogenous target mimics (eTMs) can bind miRNAs to regulate the expressions of target messenger RNAs (mRNAs). A growing number of studies focus on animals, but the studies on plants are scarce and many functions of plant eTMs are unknown. This study proposes a novel ensemble pruning protocol for predicting plant miRNA-lncRNA interactions at first. It adaptively prunes the base models based on dual-path parallel ensemble method to meet the challenge of cross-species prediction. Then potential eTMs are mined from predicted results. The expression levels of RNAs are identified through biological experiment to construct the lncRNA-miRNA-mRNA regulatory network, and the functions of potential eTMs are inferred through enrichment analysis. Experiment results show that the proposed protocol outperforms existing methods and state-of-the-art predictors on various plant species. A total of 17 potential eTMs are verified by biological experiment to involve in 22 regulations, and 14 potential eTMs are inferred by Gene Ontology enrichment analysis to involve in 63 functions, which is significant for further research., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are both non-coding RNAs (ncRNAs) and their interactions play important roles in biological processes. Computational methods, such as machine learning and various bioinformatics tools, can predict potential miRNA-lncRNA interactions, which is significant for studying their mechanisms and biological functions. A growing number of RNA interaction predictors for animal have been reported, but they are unreliable for plant due to the differences of ncRNAs in animal and plant. It is urgent to build a reliable plant predictor, especially for cross-species. This paper proposes an ensemble deep learning model based on multi-level information enhancement and greedy fuzzy decision (PmliPEMG) for plant miRNA-lncRNA interaction prediction. The fusion complex features, multi-scale convolutional long short-term memory networks, and attention mechanism are adopted to enhance the sample information at the feature, scale, and model levels, respectively. An ensemble deep learning model is built based on a novel method (greedy fuzzy decision) which greatly improves the efficiency. The multi-level information enhancement and greedy fuzzy decision are verified to have the positive effects on prediction performance. PmliPEMG can be applied to the cross-species prediction. It shows better performance and stronger generalization ability than state-of-the-art predictors and may provide valuable references for related research., (© 2021. International Association of Scientists in the Interdisciplinary Areas.)

Objective: To illustrate the biological function of long non-coding RNA (lncRNA) SNHG3 in the deterioration of colorectal cancer (CRC) by regulating the miR-370-5p/EZH1 axis., Patients and Methods: SNHG3 levels in fifty pairs of CRC and non-tumor tissues were examined by quantitative real-time polymerase chain reaction (qRT-PCR). Its correlation to tumor staging, lymph node metastasis and prognosis of CRC was analyzed. Cell counting kit-8 (CCK-8) and 5-Ethynyl-2'- deoxyuridine (EdU) assay were conducted to assess the influence of SNHG3 on CRC cell proliferation in vitro. In addition, invasive ability of CRC cells transfected with si-SNHG3 was explored by transwell assay. The binding and regulatory relations in the SNHG3/miR-370-5p/EZH1 axis were ascertained by Dual-Luciferase reporter assay., Results: SNHG3 was upregulated in CRC tissues and cell lines. Its high level was correlated to advanced tumor staging, positive lymph node metastasis and poor prognosis of CRC. Knockdown of SNHG3 reduced proliferative and invasive rates of SW480 and HT29 cells. The SNHG3/miR-370-5p/EZH1 axis was ascertained. In addition, knockdown of miR-370-5p enhanced proliferative and invasive rates of SW480 and HT29 cells., Conclusions: LncRNA SNHG3 induces proliferative and invasive potentials of CRC by regulating the miR-370-5p/EZH1 axis.

Long non-coding RNAs (lncRNAs) have been found to play critical roles in regulating gene expression, but their function in translational control is poorly understood. We found lnc-OPHN1-5, which lies close to the androgen receptor (AR) gene on chromosome X, increased prostate cancer (PCa) Enzalutamide (Enz) sensitivity via decreasing AR protein expression and associated activity. Mechanism dissection revealed that lnc-OPHN1-5 interacted with AR-mRNA to minimize its interaction with the RNA binding protein (RBP) hnRNPA1. Suppressing lnc-OPHN1-5 expression promoted the interaction between AR-mRNA and hnRNPA1, followed by an increase of ribosome association with AR-mRNA and translation. This effect was reversed by increasing lnc-OPHN1-5 expression. Consistently, the in vivo mice model confirmed that knocking down lnc-OPHN1-5 expression in tumors significantly increased the tumor formation rate and AR protein expression compared with the control group. Furthermore, knocking down hnRNPA1 blocked/reversed shlnc-OPHN1-5-increased AR protein expression and re-sensitized cells to Enz treatment efficacy. Evidence from Enz-resistant cell lines, patient-derived xenograft (PDX) models, clinical samples, and a human PCa study accordantly suggested that patients with low expression of lnc-OPHN1-5 likely have unfavorable prognoses and probably are less sensitive to Enz treatment. In summary, targeting this newly identified lnc-OPHN1-5/AR/hnRNPA1 complex may help develop novel therapies to increase Enz treatment sensitivity for suppressing the PCa at an advanced stage., (© 2021. The Author(s).)

Background: Plant long non-coding RNAs (lncRNAs) play vital roles in many biological processes mainly through interactions with RNA-binding protein (RBP). To understand the function of lncRNAs, a fundamental method is to identify which types of proteins interact with the lncRNAs. However, the models or rules of interactions are a major challenge when calculating and estimating the types of RBP., Results: In this study, we propose an ensemble deep learning model to predict plant lncRNA-protein interactions using stacked denoising autoencoder and convolutional neural network based on sequence and structural information, named PRPI-SC. PRPI-SC predicts interactions between lncRNAs and proteins based on the k-mer features of RNAs and proteins. Experiments proved good results on Arabidopsis thaliana and Zea mays datasets (ATH948 and ZEA22133). The accuracy rates of ATH948 and ZEA22133 datasets were 88.9% and 82.6%, respectively. PRPI-SC also performed well on some public RNA protein interaction datasets., Conclusions: PRPI-SC accurately predicts the interaction between plant lncRNA and protein, which plays a guiding role in studying the function and expression of plant lncRNA. At the same time, PRPI-SC has a strong generalization ability and good prediction effect for non-plant data., (© 2021. The Author(s).)

Lung adenocarcinoma (LUAD) is a major subtype of non-small-cell lung cancers (NSCLC). LINC00680 has been characterized as a novel oncogenic lncRNA in LUAD, but its regulatory mechanisms remain largely unclear. This study aimed to explore the subcellular localization of LINC00680 in LUAD and its regulation on the transcriptional process. LUAD cell lines (A549, H1650, and H1299) were used for in vitro and in vivo studies. Results showed LINC00680 depletion resulted in G0/G1 phase arrest of LUAD cells and reduced CDK4 and cyclin D1 expression in H1650 and H1299 cells. LINC00680 overexpression promoted A549 cell proliferation and increased CDK4 and cyclin D1 expression. RNA-fluorescence in situ hybridization (FISH) assay showed that LINC00680 has both cytoplasmic and nuclear distribution in LUAD cells. RNA pulldown and western blotting assays confirmed a physical interaction between LINC00680 and GATA6. In LUAD cells, GATA6 overexpression only slightly suppressed SOX12 transcription. ChIP-qPCR and dual-luciferase assay showed that GATA6 only weakly bound to the SOX12 promoter and decreased its activity. However, when LINC00680 was depleted, these transcriptional suppressive effects were significantly enhanced. These findings suggested that LINC00680 forms a complex with GATA6 and weakens its transcriptional suppressive effect on SOX12 expression. In the nude mice model, LINC00680 overexpression partly abrogated the growth-suppressive effects of GATA6 on A549 derived tumors. In summary, this study revealed a novel LINC00680-GATA6-SOX12 axis in promoting LUAD cell cycle progression and proliferation. Future studies should be conducted for a better understanding of the complex networking of LINC00680 in LUAD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Long noncoding RNAs (lncRNAs) play an important role in regulating biological activities and their prediction is significant for exploring biological processes. Long short-term memory (LSTM) and convolutional neural network (CNN) can automatically extract and learn the abstract information from the encoded RNA sequences to avoid complex feature engineering. An ensemble model learns the information from multiple perspectives and shows better performance than a single model. It is feasible and interesting that the RNA sequence is considered as sentence and image to train LSTM and CNN respectively, and then the trained models are hybridized to predict lncRNAs. Up to present, there are various predictors for lncRNAs, but few of them are proposed for plant. A reliable and powerful predictor for plant lncRNAs is necessary., Results: To boost the performance of predicting lncRNAs, this paper proposes a hybrid deep learning model based on two encoding styles (PlncRNA-HDeep), which does not require prior knowledge and only uses RNA sequences to train the models for predicting plant lncRNAs. It not only learns the diversified information from RNA sequences encoded by p-nucleotide and one-hot encodings, but also takes advantages of lncRNA-LSTM proposed in our previous study and CNN. The parameters are adjusted and three hybrid strategies are tested to maximize its performance. Experiment results show that PlncRNA-HDeep is more effective than lncRNA-LSTM and CNN and obtains 97.9% sensitivity, 95.1% precision, 96.5% accuracy and 96.5% F1 score on Zea mays dataset which are better than those of several shallow machine learning methods (support vector machine, random forest, k-nearest neighbor, decision tree, naive Bayes and logistic regression) and some existing tools (CNCI, PLEK, CPC2, LncADeep and lncRNAnet)., Conclusions: PlncRNA-HDeep is feasible and obtains the credible predictive results. It may also provide valuable references for other related research.

Codonopsis pilosula is a type of traditional Chinese medicine that exerts an anti‑aging effect and can regulate the gastrointestinal (GI) system. The aim of the present study was to investigate the underlying molecular mechanisms responsible for the anti‑aging effects of Codonopsis pilosula in the GI tract of mice with D‑galactose‑induced aging. First, a successful mouse model of aging was established, and Codonopsis pilosula water extract was then used for treatment. The anti‑aging effects of Codonopsis pilosula on the GI tract were then detected from the perspectives of tissue structure, physiological function and cell ultrastructure. Finally, in order to explore the underlying molecular mechanisms, the expression profiles of lncRNAs and mRNAs in the stomach and intestine were examined using microarray technology. A total of 117 (41 lncRNAs and 76 mRNAs) and 168 (85 lncRNA sand 83 mRNAs) differentially expressed genes associated with the anti‑aging effects of Codonopsis pilosula were identified in the stomach and intestine, respectively. Through integrated analysis of the stomach and intestine, 4 hub RNAs, including 1 lncRNA (LOC105243318) and 3 mRNAs (Fam132a, Rorc and 1200016E24Rik) were identified, which may be associated with the anti‑aging effects of Codonopsis pilosula in the GI tract of aging mice. The Kyoto Encyclopedia of Genes and Genomes analysis revealed that the metabolic pathway was an important pathway underlying the anti‑aging effects of Codonopsis pilosula in the GI tract. On the whole, in the present study, 4 hub RNAs associated with these effects and their regulatory networks were found in the GI tract of aging mice. In addition, the metabolic pathway was found to play an important role in these anti‑aging effects in the GI tract.

While the androgen receptor (AR) may influence the progression of clear cell renal cell carcinoma (ccRCC), its role to impact vasculogenic mimicry (VM) to alter the ccRCC progression and metastasis remains obscure. Here, we demonstrated that elevated AR expression was positively correlated with tumor-originated vasculogenesis in ccRCC patients. Consistently, in vitro research revealed AR promoted VM formation in ccRCC cell lines via modulating lncRNA-TANAR/TWIST1 signals. Mechanism dissection showed that AR could increase lncRNA-TANAR (TANAR) expression through binding to the androgen response elements (AREs) located in its promoter region. Moreover, we found that TANAR could impede nonsense-mediated mRNA decay (NMD) of TWIST1 mRNA by direct interaction with TWIST1 5'UTR. A preclinical study using in vivo mouse model with orthotopic xenografts of ccRCC cells further confirmed the in vitro data. Together, these results illustrated that AR-mediated TANAR signals might play a crucial role in ccRCC VM formation and metastasis, and targeting this newly identified AR/TANAR/TWIST1 signaling may help in the development of a novel anti-angiogenesis therapy to better suppress the ccRCC progression.

N 6-Methyladenosine (m6A) is the most prevalent RNA modification on mRNAs and lncRNAs. It plays a pivotal role during various biological processes and disease pathogenesis. We present here a comprehensive knowledgebase, m6A-Atlas, for unraveling the m6A epitranscriptome. Compared to existing databases, m6A-Atlas features a high-confidence collection of 442 162 reliable m6A sites identified from seven base-resolution technologies and the quantitative (rather than binary) epitranscriptome profiles estimated from 1363 high-throughput sequencing samples. It also offers novel features, such as; the conservation of m6A sites among seven vertebrate species (including human, mouse and chimp), the m6A epitranscriptomes of 10 virus species (including HIV, KSHV and DENV), the putative biological functions of individual m6A sites predicted from epitranscriptome data, and the potential pathogenesis of m6A sites inferred from disease-associated genetic mutations that can directly destroy m6A directing sequence motifs. A user-friendly graphical user interface was constructed to support the query, visualization and sharing of the m6A epitranscriptomes annotated with sites specifying their interaction with post-transcriptional machinery (RBP-binding, microRNA interaction and splicing sites) and interactively display the landscape of multiple RNA modifications. These resources provide fresh opportunities for unraveling the m6A epitranscriptomes. m6A-Atlas is freely accessible at: www.xjtlu.edu.cn/biologicalsciences/atlas., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Long non-coding RNA FGD5 antisense RNA 1 (FGD5-AS1), identified to be a carcinogenic lncRNA, exhibits a regulatory role in some malignancies including non-small cell lung cancer (NSCLC). The aim of the present research is to decipher the function and underlying mechanism of FGD5-AS1 in progression of NSCLC., Methods: Expression of FGD5-AS1, miR-493-5p and DEAD-box protein 5 (DDX5) in NSCLC tissues and cells was quantified utilizing qRT-PCR. Cell proliferation was assessed by CCK-8 method. Scratch healing test and Transwell assay were used for assaying cell migration and invasion. Expressions of DDX5 and epithelial-mesenchymal transition (EMT)-related proteins were examined by Western blot. Additionally, targeting relationships between FGD5-AS1 and miR-493-5p, miR-493-5p and DDX5 were verified by dual-luciferase reporter gene assay., Results: Expression of FGD5-AS1 in NSCLC tissues and cell lines was up-regulated. Expression of FGD5-AS1 was in association with enlarged tumor size and lymph node metastasis of the patients. Knockdown of FGD5-AS1 led to the inhibition of proliferation, migration, invasion and EMT of NSCLC cells. FGD5-AS1 directly targeted miR-493-5p, while DDX5 was the target of miR-493-5p in NSCLC cells. Additionally, FGD5-AS1 could positively regulate the expression of DDX5 via suppressing miR-493-5p., Conclusion: FGD5-AS1 facilitates the proliferation, migration, invasion and EMT of NSCLC cells by sponging miR-493-5p and up-regulating DDX5.

Lung cancer is a global disease and a major cause of cancer-related mortality worldwide. Accumulated studies have confirmed the essential role of long non-coding RNAs (lncRNAs) in the occurrence and development of cancers. Meanwhile, there have been reports concerning the role of Small Nucleolar RNA Host Gene 3 (SNHG3) in various cancers. However, there are so far few studies on the function and mechanism of SNHG3 in lung cancer. In the present study, SNHG3 was found to be highly expressed in lung cancer tissues and cells. Downregulation of SNHG3 could inhibit cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) process. In addition, SNHG3 was found to have the ability to bind to miR-515-5p. Furthermore, Small Ubiquitin Like Modifier 2 (SUMO2) was identified to be the downstream target of miR-515-5p, which was negatively correlated with miR-515-5p expression. SNHG3 could positively regulate SUMO2 expression by sponging miR-515-5p. In addition, the rescue experiment showed that simultaneous transfection of miR-515-5p or SUMO2 siRNA could reverse the effect of SNHG3 expression on cell proliferation and metastasis. Collectively, our study demonstrates that SNHG3 can act on miR-515-5p in the form of competitive endogenous RNA (ceRNA) to regulate SUMO2 positively and thus affect the proliferation and metastasis of NSCLC cells. Findings in our study support that SNHG3/miR-515-5p/SUMO2 regulatory axis may become a potential therapeutic target for lung cancer.

Recent studies have identified neuroinflammation as a significant contributor to the pathological process of traumatic brain injury (TBI) and as a potentially effective target for treatment. LncRNA maternally expressed gene 3 (Meg3) has further been observed to play a critical role in diverse biological processes, including microglial activation and the inflammatory response. However, its target gene and associated signaling pathway require further elucidation. This study found that lipopolysaccharide + ATP upregulated Meg3, promoted microglia activation, Nlrp3/caspase1 activation and inflammation, and markedly reduced miR-7a-5p. Overexpression of miR-7a-5p attenuated Meg3-induced microglial activation, but not Meg3 expression. Bioinformatic analysis and dual-luciferase assays indicated that Meg3 was a direct target of miR-7a-5p that negatively regulates miR-7a-5p expression. Further, we showed that Meg3 acted as a competing endogenous RNA for miR-7a-5p and induced microglial inflammation by regulating nod-like receptor protein 3 (Nlrp3) expression. Our study thus demonstrates Meg3 regulates microglia inflammation by targeting the miR-7a-5p /Nlrp3 pathway., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Key Message: The complex interplay among sRNAs, lncRNAs and circRNAs has been implicated in plants under biotic and abiotic stresses. Here, we review current advances in our understanding of ncRNA interactions and links, which have considerable potential for improving the agronomic traits and the environmental adaptability of plants. Plants can respond to biotic or abiotic stresses. To cope with various conditions, numerous intricate molecular regulatory mechanisms have evolved in plants. Noncoding RNAs (ncRNAs) can be divided into small noncoding RNAs (sRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs). Emerging evidence has demonstrated that interplay among the ncRNAs acts as a novel layer in the regulatory mechanisms, which has attracted substantial interest. Links between sRNAs can affect plant immune responses and development in synergistic or antagonistic manners. Additionally, multiple interactions between lncRNAs and sRNAs are involved in crop breeding, disease resistance and high tolerance to environmental stresses. Here, we summarize current knowledge of the interactions and links among the ncRNAs in plant responses to stresses and the methods for identifying ncRNA interactions. Furthermore, challenges and prospects for further progress in elucidating ncRNA interactions and links are highlighted.

Current reports refer to the role of long noncoding RNA (lncRNA) prostate androgen-regulated transcript 1 (PART1) as a tumor suppressor in some types of cancer but as an oncogene in other kinds of cancer. In gastric cancer, it had been reported to be downregulated. However, the clinical significance and underlying mechanism of PART1 function in gastric cancer remains undefined. Here, seven differential expression levels of noncoding RNAs (DE-lncRNAs) were screened from gastric cancer through a probe reannotation of a human exon array. PART1 was selected for further study because of its high fold change number. In our cohort, PART1 was identified as a significant downregulated lncRNA in gastric cancer tissues by qPCR and in situ hybridization (ISH), and its low expression was significantly correlated with postoperative metastasis and short overall survival time after surgery. Through the results of gain-of-function experiments, PART1 was confirmed as a tumor suppressor that can decrease not only cell viability, migration, and invasion in vitro but also tumorigenesis and tumor metastasis in vivo. Mechanistically, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) showed that PART1 interacts with androgen receptor (AR), and then, promyelocytic leukemia zinc finger (PLZF) is upregulated in an androgen-independent manner. In a chain reaction, chromatin immunoprecipitation (ChIP) assay additionally illustrated that PLZF upregulation increased the enrichment of EZH2 and H3K27 trimethylation in the platelet-derived growth factor (PDGFB) promotor, thereby inhibition of PDGFB and the subsequent PDGFRβ/PI3K/Akt signaling pathway. Based on these findings, we showed PART1 plays a tumor suppressor role by promoting PLZF expression followed by recruitment of EZH2 to mediate epigenetic PDGFB silencing and downstream PI3K/Akt inhibition, suggesting that PART1 has a key role in restraining the aggressive ability of GC cells and providing a novel perspective on lncRNAs in GC progression.

Cervical cancer is a female cancer with the second highest motility over the world. It is urgent to find new therapeutic methods based on long-coding RNAs and microRNAs. UCA1 was proved to be related with many human cancer types, but limited researches have been performed for the inner associations between UCA1 and cervical cancer. Eighty females who were undergoing surgeries were recruited for study in our research. We took the cervical cancer tissues and cells from them. Massive experiments and analysis were conducted to investigate the gene expressions and protein expressions about UCA1, KIF20A, and miR-204 in normal cells and cancer cells. The techniques contain real-time PCR, migration/invasion assay, western blot, in vivo experiments, and so on.We found that UCA1 expression was greatly up-regulated in cervical cancer tissues and cell lines. Our in vitro assays revealed that the suppressing of UCA1 could reduce cervical cancer cells proliferation, migration, and invasion. In addition, we found that lncRNA UCA1 could sponge miR-204 and promote the proliferation and invasion of cervical cancer cells via the up-regulating of KIF20A expression. As a result, the inhibiting of UCA1 could lower cervical cancer (CC) cells growth rate in vivo.Our results identified that UCA1 could serve as an oncogene in cervical cancer cell progression through the modulating of miR-204/KIF20A axis. It gives novel insights to the searching of novel therapeutic methods for cervical cancer.

Long non-coding RNAs (lncRNAs) play key roles in regulating cellular biological processes through diverse molecular mechanisms including binding to RNA binding proteins. The majority of plant lncRNAs are functionally uncharacterized, thus, accurate prediction of plant lncRNA-protein interaction is imperative for subsequent functional studies. We present an integrative model, namely DRPLPI. Its uniqueness is that it predicts by multi-feature fusion. Structural and four groups of sequence features are used, including tri-nucleotide composition, gapped k-mer, recursive complement and binary profile. We design a multi-head self-attention long short-term memory encoder-decoder network to extract generative high-level features. To obtain robust results, DRPLPI combines categorical boosting and extra trees into a single meta-learner. Experiments on Zea mays and Arabidopsis thaliana obtained 0.9820 and 0.9652 area under precision/recall curve (AUPRC) respectively. The proposed method shows significant enhancement in the prediction performance compared with existing state-of-the-art methods., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Long non-coding RNAs (lncRNAs) play a broad spectrum of distinctive regulatory roles through interactions with proteins. However, only a few plant lncRNAs have been experimentally characterized. We propose GPLPI, a graph representation learning method, to predict plant lncRNA-protein interaction (LPI) from sequence and structural information. GPLPI employs a generative model using long short-term memory (LSTM) with graph attention. Evolutionary features are extracted using frequency chaos game representation (FCGR). Manifold regularization and l 2 -norm are adopted to obtain discriminant feature representations and mitigate overfitting. The model captures locality preserving and reconstruction constraints that lead to better generalization ability. Finally, potential interactions between lncRNAs and proteins are predicted by integrating catboost and regularized Logistic regression based on L-BFGS optimization algorithm. The method is trained and tested on Arabidopsis thaliana and Zea mays datasets. GPLPI achieves accuracies of 85.76% and 91.97% respectively. The results show that our method consistently outperforms other state-of-the-art methods.

Long non-coding RNAs (lncRNAs) are involved in the resistance of plants to infection by pathogens via interactions with microRNAs (miRNAs). Long non-coding RNAs are cleaved by miRNAs to produce phased small interfering RNAs (phasiRNAs), which, as competing endogenous RNAs (ceRNAs), function as decoys for mature miRNAs, thus inhibiting their expression, and contain pre-miRNA sequences to produce mature miRNAs. However, whether lncRNAs and miRNAs mediate other molecular mechanisms during plant resistance to pathogens is unknown. In this study, as a positive regulator, Sl-lncRNA15492 from tomato (Solanum lycopersicum Zaofen No. 2) plants affected tomato resistance to Phytophthora infestans. Gain- and loss-of-function experiments and RNA ligase-mediated 5'-amplification of cDNA ends (RLM-5' RACE) also revealed that Sl-miR482a was negatively involved in tomato resistance by targeting Sl-NBS-LRR genes and that silencing of Sl-NBS-LRR1 decreased tomato resistance. Sl-lncRNA15492 inhibited the expression of mature Sl-miR482a, whose precursor was located within the antisense sequence of Sl-lncRNA15492. Further degradome analysis and additional RLM-5' RACE experiments verified that mature Sl-miR482a could also cleave Sl-lncRNA15492. These results provide a mechanism by which lncRNAs might inhibit precursor miRNA expression through antisense strands of lncRNAs, and demonstrate that Sl-lncRNA15492 and Sl-miR482a mutually inhibit the maintenance of Sl-NBS-LRR1 homeostasis during tomato resistance to P. infestans., (© 2020 Society for Experimental Biology and John Wiley & Sons Ltd.)

Background: Long noncoding RNAs (lncRNAs), which are typically > 200 nt in length, are involved in numerous biological processes. Studies on lncRNAs in the cultivated peanut (Arachis hypogaea L.) largely remain unknown., Results: A genome-wide scan of the peanut (Arachis hypogaea L.) transcriptome identified 1442 lncRNAs, which were encoded by loci distributed over every chromosome. Long intergenic noncoding RNAs accounted for 85.58% of these lncRNAs. Additionally, 189 lncRNAs were differentially abundant in the root, leaf, or seed. Generally, lncRNAs showed lower expression levels, tighter tissue-specific expression, and less splicing than mRNAs. Approximately 44.17% of the lncRNAs with an exon/intron structure were alternatively spliced; this rate was slightly lower than the splicing rate of mRNA. Transcription at the start site event was the alternative splicing (AS) event with the highest frequency (28.05%) in peanut lncRNAs, whereas the occurrence rate (30.19%) of intron retention event was the highest in mRNAs. AS changed the target gene profiles of lncRNAs and increased the diversity and flexibility of lncRNAs, which may be important for lncRNAs to execute their functions. Additionally, a substantial number of the peanut AS isoforms generated from protein-encoding genes appeared to be noncoding because they were truncated transcripts; such isoforms can be legitimately regarded as a class of lncRNAs. The predicted target genes of the lncRNAs were involved in a wide range of biological processes. Furthermore, expression pattern of several selected lncRNAs and their target genes were examined under salt stress, results showed that all of them could respond to salt stress in different manners., Conclusions: This study provided a resource of candidate lncRNAs and expression patterns across tissues, and whether these lncRNAs are functional will be further investigated in our subsequent experiments.

Motivation: The studies have indicated that not only microRNAs (miRNAs) or long non-coding RNAs (lncRNAs) play important roles in biological activities, but also their interactions affect the biological process. A growing number of studies focus on the miRNA-lncRNA interactions, while few of them are proposed for plant. The prediction of interactions is significant for understanding the mechanism of interaction between miRNA and lncRNA in plant., Results: This article proposes a new method for fulfilling plant miRNA-lncRNA interaction prediction (PmliPred). The deep learning model and shallow machine learning model are trained using raw sequence and manually extracted features, respectively. Then they are hybridized based on fuzzy decision for prediction. PmliPred shows better performance and generalization ability compared with the existing methods. Several new miRNA-lncRNA interactions in Solanum lycopersicum are successfully identified using quantitative real time-polymerase chain reaction from the candidates predicted by PmliPred, which further verifies its effectiveness., Availability and Implementation: The source code of PmliPred is freely available at http://bis.zju.edu.cn/PmliPred/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Melon (Cucumis melo L.), an economically beneficial crop widely cultivated around the world, is vulnerable to powdery mildew (PM). However, the studies on molecular mechanism of melon response to PM fungi is still limited. Long non coding RNAs (lncRNAs) have emerged as new regulators in plants response to biotic stresses. We predicted and identified the intricate regulatory roles of lncRNAs in melon response to PM fungi. A total of 539 lncRNAs were identified from PM-resistant (MR-1) and susceptible melon (Top Mark), in which 254 were significantly altered after PM fungi infection. Multiple target genes of lncRNAs were found to be involved in the hydrolysis of chitin, callose deposition and cell wall thickening, plant-pathogen interaction and plant hormone signal transduction pathway. Additionally, a total of 42 lncRNAs possess the various functions with microRNAs (miRNAs), including lncRNAs that are targeted by miRNAs and function as miRNA precursors or miRNA sponges. These findings provide a comprehensive view of potentially functional lncRNAs, corresponding target genes and related lncRNA-miRNA pairs, which will greatly increase our knowledge of the mechanism underlying susceptibility and resistance to PM in melon., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Gliomas are complex and heterogeneous brain tumors with poor prognosis. Glioma cells can communicate with their surroundings to create a tumor-permissive microenvironment. Exosomes represent a new means of intercellular communication by delivering various bioactive molecules, including proteins, lipids and nucleic acids, and participate in tumor initiation and progression. Noncoding RNAs (ncRNAs) including microRNA, long-noncoding RNA, and circular RNA, account for a large portion of human transcriptome and play important roles in various pathophysiological processes, especially in cancers. In addition, ncRNAs can be selectively packaged, secreted and transferred between cells in exosomes and modulate numerous hallmarks of glioma, such as proliferation, invasion, angiogenesis, immune-escape, and treatment resistance. Hence, the strategies of specifically targeting exosomal ncRNAs could be attractive therapeutic options. Exosomes are able to cross the blood brain barrier (BBB), and are readily accessible in nearly all types of human biofluids, which make them the promising biomarkers for gliomas. Additionally, given the biocompatibility of exosomes, they can be engineered to deliver therapeutic factors, such as RNA, proteins and drugs, to target cells for therapeutic applications. Here, we reviewed current research on the roles of exosomal ncRNAs in glioma progression. We also discussed their potential clinical applications as novel biomarkers and therapeutics.

Non-coding RNA (ncRNA) plays an important role in regulating biological activities of animals and plants, and the representative ones are microRNA (miRNA) and long non-coding RNA (lncRNA). Recent research has found that predicting the interaction between miRNA and lncRNA is the primary task for elucidating their functional mechanisms. Due to the small scale of data, a large amount of noise, and the limitations of human factors, the prediction accuracy and reliability of traditional feature-based classification methods are often affected. Besides, the structure of plant ncRNA is complex. This paper proposes an ensemble deep-learning model based on convolutional neural network (CNN) and independently recurrent neural network (IndRNN) for predicting the interaction between miRNA and lncRNA of plants, namely, CIRNN. The model uses CNN to explore the functional features of gene sequences automatically, leverages IndRNN to obtain the representation of sequence features, and learns the dependencies among sequences; thus, it overcomes the inaccuracy caused by human factors in traditional feature engineering. The experiment results show that the proposed model is superior to shallow machine-learning and existing deep-learning models when dealing with large-scale data, especially for the long sequence.

Our previous studies have revealed the function of long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) in tomato in response to Phytophthora infestans infection. However, the interaction relationships between lncRNAs and miRNAs during tomato resistance to P. infestans infection are unknown. In this study, 9,011 lncRNAs were identified from tomato plants, including 115 upregulated and 81 downregulated lncRNAs. Among these, 148 were found to be differentially expressed and might affect the expression of 771 genes, which are composed of 887 matched lncRNA-mRNA pairs. In total, 88 lncRNAs were identified as endogenous RNAs (ceRNAs) and predicted to decoy 46 miRNAs. Degradome sequencing revealed that 11 miRNAs that were decoyed by 20 lncRNAs could target 30 genes. These lncRNAs, miRNAs, and target genes were predicted to form 10 regulatory modules. Among them, lncRNA42705/lncRNA08711, lncRNA39896, and lncRNA11265/lncRNA15816 might modulate MYB, HD-Zip, and NAC transcription factors by decoying miR159, miR166b, and miR164a-5p, respectively. Upon P. infestans infection, the expression levels of lncRNA42705 and lncRNA08711 displayed a negative correlation with the expression level of miR159 and a positive correlation with the expression levels of MYB genes. Tomato plants in which lncRNA42705 and lncRNA08711 were silenced displayed increased levels of miR159 and decreased levels of MYB, respectively. The result demonstrated that lncRNAs might function as ceRNAs to decoy miRNAs and affect their target genes in tomato plants, increasing resistance to disease.

Objective: The aim of this study was to investigate the expression characteristics of lncRNA CRNDE in Wilms' tumor and to further investigate whether it could promote the development of Wilms' tumor via regulating microRNA-424., Patients and Methods: Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was performed to examine the expression level of CRNDE in tumor tissues and para-cancerous tissues of patients with Wilms' tumor. Meanwhile, the expression of CRNDE in Wilms' tumor cell lines was analyzed as well. CRNDE overexpression and knockdown models were constructed using lentivirus transfection in HFWT and 17-94 cell lines, respectively. Subsequently, cell counting kit-8 (CCK-8), cell colony formation, and transwell assays were performed to explore the influence of CRNDE on the biological functions of Wilms' tumor cells. Furthermore, luciferase reporter gene assay and cell reversal experiment were applied to explore the interplay between CRNDE and microRNA-424., Results: RT-qPCR results revealed that the expression level of lncRNA CRNDE in tumor tissues of patients with Wilms' tumor was remarkably higher than that of adjacent normal tissues. Also, the difference was statistically significant (p<0.05). Compared with patients with low expression of CRNDE, the risk of lymph node metastasis was significantly higher in patients with high CRNDE expression (p<0.05). Similarly, compared with control group, the proliferation and metastasis abilities of cells in CRNDE knockdown group were remarkably down-regulated (p<0.05). However, opposite results were observed in CRNDE overexpression group. In addition, our results demonstrated that microRNA-424 expression was negatively correlated with CRNDE expression in Wilms' tumor tissues. Luciferase reporter gene assay indicated that CRNDE could be targeted by microRNA-424 through specific a binding site, further regulating the malignant progression of Wilms' tumor., Conclusions: CRNDE was highly expressed in Wilms' tumor tissue and cell lines. The expression of CRNDE was correlated with the incidence rate of lymph node metastasis in patients with Wilms' tumor. In addition, CRNDE might accelerate the progression of Wilms' tumor via modulating microRNA-424.