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Long noncoding rna-Maternally Expressed Gene 3 Contributes to Hypoxic Pulmonary Hypertension

MOLECULAR THERAPY 2019年第12期27卷 2166-2181页

作者： Xing, Yan Zheng, Xiaodong Fu, Yao Qi, Jing Li, Minghui Ma, Mingfei Wang, Shuang Li, Shuzhen Zhu, Daling Harbin Med Univ Daqing Dept Pharmacol Daqing 163319 Heilongjiang Peoples R China Harbin Med Univ Daqing Dept Genet & Cell Biol Daqing 163319 Heilongjiang Peoples R China Harbin Med Univ Coll Pharm Harbin 150081 Heilongjiang Peoples R China Harbin Med Univ Daqing Dept Pharmaceut Daqing 163319 Heilongjiang Peoples R China Harbin Med Univ Coll Pharm Dept Biopharmaceut Sci Harbin 150086 Heilongjiang Peoples R China Harbin Med Univ Daqing Cent Lab Daqing 163319 Peoples R China State Prov Key Labs Biomed Pharmaceut China Daqing 163319 Peoples R China Harbin Med Univ Minist Educ Key Lab Cardiovasc Med Res Harbin 150081 Heilongjiang Peoples R China

The expression and function of long noncoding rnas (lncrnas) in the development of hypoxic pulmonary hypertension (HPH), especially in the proliferation of pulmonary artery smooth muscle cells (PASMCs), are largely unknown. Herein, we examined the expression and role of lncrna-maternally expressed gene 3 (lncrna-MEG3) in HPH. lncrna-MEG3 was significantly increased and primarily localized in the cytoplasm of hypoxic PASMCs. lncrna-MEG3 knockdown by lung-specific delivery of small interfering rnas (sirnas) significantly inhibited the development of HPH in vivo. Silencing of lncrna-MEG3 by sirnas and gapmers attenuated proliferation and cell-cycle progression in both PASMCs from idiopathic pulmonary arterial hypertension (iPAH) patients (iPAH-PASMCs) and hypoxia-exposed PASMCs in vitro. Mechanistically, we found that lncrna-MEG3 interacts with and leads to the degradation of microrna-328-3p (miR-3283p), leading to upregulation of insulin-like growth factor 1 receptor (IGF1R). Additionally, higher expression of lncrnaMEG3 and IGF1R and lower expression of miR-328-3p were observed in iPAH-PASMCs and relevant HPH models. These data provide insights into the contribution of lncrna-MEG3 to HPH. Upregulation of lncrna-MEG3 sequesters cytoplasmic miR-328-3p, eventually leading to expression of IGF1R, revealing a regulatory mechanism by lncrnas in hypoxia-induced PASMC proliferation.

关键词： noncoding rna maternally expressed gene 3 hypoxic pulmonary hypertension proliferation microrna-328 insulin-like growth factor 1 receptor

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Methyltransferase-like protein 16 binds the 3′-terminal triple helix of MALAT1 long noncoding rna

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2016年第49期113卷 14013-14018页

作者： Brown, Jessica A. Kinzig, Charles G. DeGregorio, Suzanne J. Steitz, Joan A. Yale Univ Sch Med Howard Hughes Med Inst Dept Mol Biophys & Biochem 333 Cedar St New Haven CT 06536 USA

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a cancer-promoting long noncoding rna, accumulates in cells by using a 3'-triple-helical rna stability element for nuclear expression (ENE). The ENE, a stem-loop structure containing a U-rich internal loop, interacts with a downstream A-rich tract (ENE+A) to form a blunt-ended triple helix composed of nine U.A-U triples interrupted by a C.G-C triple and C-G doublet. This unique structure prompted us to explore the possibility of protein binding. Native gel-shift assays revealed a shift in radiolabeled MALAT1 ENE+A rna upon addition of HEK293T cell lysate. Competitive gel-shift assays suggested that protein binding depends not only on the triple-helical structure but also its nucleotide composition. Selection from the lysate using a biotinylated-rna probe followed by mass spectrometry identified methyltransferase-like protein 16 (METTL16), a putative rna methyltransferase, as an interacting protein of the MALAT1 ENE+A. Gel-shift assays confirmed the METTL16-MALAT1 ENE+A interaction in vitro: Binding was observed with recombinant METTL16, but diminished in lysate depleted of METTL16, and a supershift was detected after adding anti-METTL16 antibody. Importantly, rna immunoprecipitation after in vivo UV cross-linking and an in situ proximity ligation assay for rna-protein interactions confirmed an association between METTL16 and MALAT1 in cells. METTL16 is an abundant (similar to 5 x 10(5) molecules per cell) nuclear protein in HeLa cells. Its identification as a triple-stranded rna binding protein supports the formation of rna triple helices inside cells and suggests the existence of a class of triple-stranded rna binding proteins, which may enable the discovery of additional cellular rna triple helices.

关键词： rna binding protein rna triple helix noncoding rna

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Identification of host rnas that interact with EBV noncoding rna EBER2

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rna BIOLOGY 2018年第9期15卷 1181-1191页

作者： Nanni, Adalena V. Lee, Nara Univ Pittsburgh Sch Med Dept Microbiol & Mol Genet 450 Technol Dr Pittsburgh PA 15219 USA

Epstein-Barr virus (EBV) expresses an abundant nuclear noncoding rna called EBER2, which interacts with and acts as a guide rna for the host transcription factor PAX5. This ribonucleoprotein complex localizes to the terminal repeat (TR) regions of the EBV genome via rna-rna interactions between EBER2 and nascent transcripts originating from these target sites. Given the fact that EBER2 base pairs with a viral rna, we developed a protocol to identify EBER2-interacting rnas in a transcriptome-wide manner. Our approach entails psoralen-mediated crosslinking, selection with antisense oligonucleotides targeting EBER2, and rnase V1 digestion coupled to next-generation sequencing. The use of rnase V1 circumvents the need of extensive computational analysis post data acquisition to search for predicted rna hybrids, as the rnase V1 cleavage site marks the region of rna duplex formation. As proof of principle, we show that our approach correctly identifies the known EBER2 interaction with TR rnas. Moreover, we identify the host functional noncoding rnas MRP, H1, and 7SL rnas as well as three putative enhancer rnas as candidate EBER2-interacting rnas. As all of these gene loci exhibit PAX5 occupancy, we propose that EBER2 is recruited to these sites through its binding partner PAX5 and forms rna-rna interactions with nascent transcripts on chromatin. Thus, our novel approach facilitates the identification of targeted rna-rna-interactions and minimizes the need of downstream computational analyses to predict rna duplexes.

关键词： Epstein-Barr virus noncoding rna rna-rna interaction next-generation sequencing

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Expression of the long noncoding rna RP11-169D4.1-001 in Hypopharyngeal Squamous cell carcinoma tissue and its clinical significance

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JOUrnaL OF CLINICAL LABORATORY ANALYSIS 2020年第1期34卷 e23019-e23019页

作者： Shen, Zhisen Wu, Linrong Hao, Wenjuan Li, Qun Zhou, Chongchang Ningbo Univ Lihuili Hosp Ningbo Med Ctr Dept Otorhinolaryngol Head & Neck Surg Ningbo Zhejiang Peoples R China Ningbo Univ Lihuili Hosp Ningbo Med Ctr Lab Otorhinolaryngol Head & Neck Surg Ningbo Zhejiang Peoples R China

Background Increased research efforts have demonstrated that lncrnas are associated with multiple head and neck tumors and play important roles in cancer. We previously found that RP11-169D4.1-001 plays a tumor-suppressive role in laryngeal cancer, but its function in human hypopharyngeal squamous cell carcinoma (HSCC) remains unknown. Thus, this research aimed to analyze the relationship between RP11-169D4.1-001 expression and HSCC clinicopathological features. Methods Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the expression of RP11-169D4.1-001 in 70 pairs of HSCC and adjacent normal tissues. Results The expression level of RP11-169D4.1-001 in HSCC tissues was significantly lower than that in adjacent normal tissues (P = .001). The expression of RP11-169D4.1-001 had no significant relationship with tumor differentiation, stage, smoking, drinking, age, tumor location, or treatment. RP11-169D4.1-001 expression was associated with T category (P = .008) and lymph node metastasis (P = .001). Survival data were assessed by Kaplan-Meier curves. Patients with high RP11-169D4.1-001 expression were found to have a shorter overall survival than patients with low RP11-169D4.1-001 expression. Multivariate analysis also indicated that target rna was an independent factor for prognosis. The ROC curve was constructed to clarify the diagnostic value of RP11-169D4.1-001. Conclusions RP11-169D4.1-001 may serve as a new biomarker and potential drug target and can be used as a new biomarker and a potential drug target for the detection and treatment of hypopharyngeal cancer, respectively. Furthermore, RP11-169D4.1-001 expression may be an independent prognostic factor affecting the survival of hypopharyngeal cancer patients.

关键词： biomarker diagnosis HSCC noncoding rna 1-001

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EBV noncoding rna EBER2 interacts with host rna-binding proteins to regulate viral gene expression

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2016年第12期113卷 3221-3226页

作者： Lee, Nara Yario, Therese A. Gao, Jessica S. Steitz, Joan A. Yale Univ Sch Med Dept Mol Biophys & Biochem 333 Cedar St New Haven CT 06536 USA Yale Univ Sch Med Howard Hughes Med Inst 333 Cedar St New Haven CT 06536 USA

Epstein-Barr virus (EBV) produces a highly abundant noncoding rna called EBV-encoded rna 2 (EBER2) that interacts indirectly with the host transcription factor paired box protein 5 (PAX5) to regulate viral latent membrane protein 1/2 (LMP1/2) gene expression as well as EBV lytic replication. To identify intermediary proteins, we isolated EBER2-PAX5-containing complexes and analyzed the protein components by mass spectrometry. The top candidates include three host proteins splicing factor proline and glutamine rich (SFPQ), non-POU domain-containing octamer-binding protein (NONO), and rna binding motif protein 14 (RBM14), all reported to be components of nuclear bodies called paraspeckles. In vivo rna-protein crosslinking indicates that SFPQ and RBM14 contact EBER2 directly. Binding studies using recombinant proteins demonstrate that SFPQ and NONO associate with PAX5, potentially bridging its interaction with EBER2. Similar to EBER2 or PAX5 depletion, knockdown of any of the three host rna-binding proteins results in the up-regulation of viral LMP2A mrna levels, supporting a physiologically relevant interaction of these newly identified factors with EBER2 and PAX5. Identification of these EBER2-interacting proteins enables the search for cellular noncoding rnas that regulate host gene expression in a manner similar to EBER2.

关键词： noncoding rna Epstein-Barr virus paraspeckle rna binding protein

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Identification and characterization of a novel nuclear noncoding rna, Fben-1, which is preferentially expressed in the higher brain center of the female silkworm moth, Bombyx mori

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NEUROSCIENCE LETTERS 2011年第3期496卷 176-180页

作者： Taguchi, Syusaku Iwami, Masafumi Kiya, Taketoshi Kanazawa Univ Grad Sch Nat Sci & Technol Div Life Sci Kanazawa Ishikawa 9201192 Japan Kanazawa Univ Grad Sch Nat Sci & Technol Div Biol Sci Kanazawa Ishikawa 9201192 Japan

Sexually dimorphic neural circuits are essential for the reproductive behavior. The molecular basis underling the sexual dimorphism, however, is still elusive in the brains of insects. To identify genes with sex-differential expression in the brain of silkworm moths, we performed fluorescent differential display screening and identified a novel gene, termed Fben-1 (Female-brain expressed noncoding rna-1), whose expression is preferential to the female brain. Fben-1 cDNA sequences contained no significant open-reading frames and comprised a sex-differential transcript composition. Expression of Fben-1 was developmentally regulated and predominant in adult female moth brains. In situ hybridization revealed that Fben-1 is mainly expressed in the cells around the mushroom bodies, a higher brain center of the insect brain. In addition, Fben-1 transcripts were localized exclusively in the nuclei of these cells. This is the first report that a long nuclear noncoding rna is expressed in a sex-differential manner in the higher center of insect brains. Our results suggest the possible involvement of nuclear noncoding rna in sexually dimorphic brain functions. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

关键词： Silkworm noncoding rna Differential display Nuclear rna Mushroom body

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Seq'ing identity and function in a repeat-derived noncoding rna world

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CHROMOSOME RESEARCH 2020年第1期28卷 111-127页

作者： O'Neill, Rachel J. Univ Connecticut Inst Syst Genom Storrs CT 06269 USA Univ Connecticut Dept Mol & Cell Biol Storrs CT 06269 USA Univ Connecticut Ctr Hlth Dept Genet & Genome Sci Farmington CT 06030 USA

Innovations in high-throughout sequencing approaches are being marshaled to both reveal the composition of the abundant and heterogeneous noncoding rnas that populate cell nuclei and lend insight to the mechanisms by which noncoding rnas influence chromosome biology and gene expression. This review focuses on some of the recent technological developments that have enabled the isolation of nascent transcripts and chromatin-associated and DNA-interacting rnas. Coupled with emerging genome assembly and analytical approaches, the field is poised to achieve a comprehensive catalog of nuclear noncoding rnas, including those derived from repetitive regions within eukaryotic genomes. Herein, particular attention is paid to the challenges and advances in the sequence analyses of repeat and transposable element-derived noncoding rnas and in ascribing specific function(s) to such rnas.

关键词： noncoding rna chromatin-associating rnas R-loop triplex repeat annotation transposable element (TE)

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Design of a small molecule against an oncogenic noncoding rna

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2016年第21期113卷 5898-5903页

作者： Velagapudi, Sai Pradeep Cameron, Michael D. Haga, Christopher L. Rosenberg, Laura H. Lafitte, Marie Duckett, Derek R. Phinney, Donald G. Disney, Matthew D. Scripps Res Inst Dept Chem Jupiter FL 33458 USA Scripps Res Inst Dept Mol Therapeut Jupiter FL 33458 USA Scripps Res Inst Dept Neurosci Jupiter FL 33458 USA

The design of precision, preclinical therapeutics from sequence is difficult, but advances in this area, particularly those focused on rational design, could quickly transform the sequence of disease-causing gene products into lead modalities. Herein, we describe the use of Inforna, a computational approach that enables the rational design of small molecules targeting rna to quickly provide a potent modulator of oncogenic microrna-96 (miR-96). We mined the secondary structure of primary microrna-96 (pri-miR-96) hairpin precursor against a database of rna motif-small molecule interactions, which identified modules that bound rnamotifs nearby and in the Drosha processing site. Precise linking of these modules together provided Targaprimir-96 (3), which selectively modulates miR-96 production in cancer cells and triggers apoptosis. Importantly, the compound is ineffective on healthy breast cells, and exogenous overexpression of pri-miR-96 reduced compound potency in breast cancer cells. Chemical Cross-Linking and Isolation by Pull-Down (Chem-CLIP), a small-molecule rna target validation approach, shows that 3 directly engages pri-miR-96 in breast cancer cells. In vivo, 3 has a favorable pharmacokinetic profile and decreases tumor burden in a mouse model of triple-negative breast cancer. Thus, rational design can quickly produce precision, in vivo bioactive lead small molecules against hard-to-treat cancers by targeting oncogenic noncoding rnas, advancing a disease-to-gene-to-drug paradigm.

关键词： rna noncoding rna drug design chemistry nucleic acids

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Top-down stepwise refinement identifies coding and noncoding rna-associated epigenetic regulatory maps in malignant glioma

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JOUrnaL OF CELLULAR AND MOLECULAR MEDICINE 2022年第8期26卷 2230-2250页

作者： Huang, Yutao Gao, Xiangyu Yang, Erwan Yue, Kangyi Cao, Yuan Zhao, Boyan Zhang, Haofuzi Dai, Shuhui Zhang, Lei Luo, Peng Jiang, Xiaofan Fourth Mil Med Univ Xijing Hosp Dept Neurosurg 169 Changle Xi Rd Xian 710032 Peoples R China Fourth Mil Med Univ State Key Lab Canc Biol Xian Peoples R China

With the emergence of the molecular era and retreat of the histology epoch in malignant glioma, it is becoming increasingly necessary to research diagnostic/prognostic/therapeutic biomarkers and their related regulatory mechanisms. While accumulating studies have investigated coding gene-associated biomarkers in malignant glioma, research on comprehensive coding and noncoding rna-associated biomarkers is lacking. Furthermore, few studies have illustrated the cross-talk signalling pathways among these biomarkers and mechanisms in detail. Here, we identified DEGs and cerna networks in malignant glioma and then constructed Cox/Lasso regression models to further identify the most valuable genes through stepwise refinement. Top-down comprehensive integrated analysis, including functional enrichment, SNV, immune infiltration, transcription factor binding site, and molecular docking analyses, further revealed the regulatory maps among these genes. The results revealed a novel and accurate model (AUC of 0.91 and C-index of 0.84 in the whole malignant gliomas, AUC of 0.90 and C-index of 0.86 in LGG, and AUC of 0.75 and C-index of 0.69 in GBM) that includes twelve ncrnas, 1 mirna and 6 coding genes. Stepwise logical reasoning based on top-down comprehensive integrated analysis and references revealed cross-talk signalling pathways among these genes that were correlated with the circadian rhythm, tumour immune microenvironment and cellular senescence pathways. In conclusion, our work reveals a novel model where the newly identified biomarkers may contribute to a precise diagnosis/prognosis and subclassification of malignant glioma, and the identified cross-talk signalling pathways would help to illustrate the noncoding rna-associated epigenetic regulatory mechanisms of glioma tumorigenesis and aid in targeted therapy.

关键词： biomarker Cox-Lasso regression cross-talk signalling epigenetic regulation integrative analysis malignant glioma noncoding rna

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The long noncoding rna landscape in hypoxic and inflammatory renal epithelial injury

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AMERICAN JOUrnaL OF PHYSIOLOGY-RENAL PHYSIOLOGY 2015年第11期309卷 F901-F913页

作者： Lin, Jennie Zhang, Xuan Xue, Chenyi Zhang, Hanrui Shashaty, Michael G. S. Gosai, Sager J. Meyer, Nuala Grazioli, Alison Hinkle, Christine Caughey, Jennifer Li, Wenjun Susztak, Katalin Gregory, Brian D. Li, Mingyao Reilly, Muredach P. Univ Penn Perelman Sch Med Renal Electrolyte & Hypertens Div Philadelphia PA 19104 USA Univ Penn Perelman Sch Med Cardiovasc Inst Philadelphia PA 19104 USA Univ Penn Dept Biol Philadelphia PA 19104 USA Univ Penn Perelman Sch Med Pulm Allergy & Crit Care Div Philadelphia PA 19104 USA Univ Penn Dept Biostat & Epidemiol Philadelphia PA 19104 USA

Long noncoding rnas (lncrnas) are emerging as key species-specific regulators of cellular and disease processes. To identify potential lncrnas relevant to acute and chronic renal epithelial injury, we performed unbiased whole transcriptome profiling of human proximal tubular epithelial cells (PTECs) in hypoxic and inflammatory conditions. rna sequencing revealed that the protein-coding and noncoding transcriptomic landscape differed between hypoxia-stimulated and cytokine-stimulated human PTECs. Hypoxia-and inflammation-modulated lncrnas were prioritized for focused followup according to their degree of induction by these stress stimuli, their expression in human kidney tissue, and whether exposure of human PTECs to plasma of critically ill sepsis patients with acute kidney injury modulated their expression. For three lncrnas (MIR210HG, linc-ATP13A4-8, and linc-KIAA1737-2) that fulfilled our criteria, we validated their expression patterns, examined their loci for conservation and synteny, and defined their associated epigenetic marks. The lncrna landscape characterized here provides insights into novel transcriptomic variations in the renal epithelial cell response to hypoxic and inflammatory stress.

关键词： noncoding rna rna sequencing hypoxia inflammation epithelial injury

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