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Screening for Small-Molecule Modulators of Long noncoding rna-Protein Interactions Using AlphaScreen

JOUrnaL OF BIOMOLECULAR SCREENING 2015年第9期20卷 1132-1141页

作者： Fatemi, Roya Pedram Salah-Uddin, Sultan Modarresi, Farzaneh Khoury, Nathalie Wahlestedt, Claes Faghihi, Mohammad Ali Univ Miami Miller Sch Med Dept Mol & Cellular Pharmacol Miami FL 33136 USA Univ Miami Miller Sch Med Dept Psychiat & Behav Sci Miami FL 33136 USA Univ Miami Miller Sch Med Ctr Therapeut Innovat Miami FL 33136 USA Univ Miami Miller Sch Med Dept Biochem & Mol Biol Miami FL 33136 USA

Long non-protein coding rnas (lncrnas) are an important class of molecules that help orchestrate key cellular events. Although their functional roles in cells are not well understood, thousands of lncrnas and a number of possible mechanisms by which they act have been reported. Lncrnas can exert their regulatory function in cells by interacting with epigenetic enzymes. In this study, we developed a tool to study lncrna-protein interactions for high-throughput screening of small-molecule modulators using AlphaScreen technology. We tested the interaction of two lncrnas: brain-derived neurotrophic factor antisense (BDNF-AS) and Hox transcript antisense rna (HOTAIR), with Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase against a phytochemical library, to look for small-molecule inhibitors that can alter the expression of downstream target genes. We identified ellipticine, a compound that up-regulates BDNF transcription. Our study shows the feasibility of using high-throughput screening to identify modulators of lncrna-protein interactions and paves the road for targeting lncrnas that are dysregulated in human disorders using small-molecule therapies.

关键词： long noncoding rna brain-derived neurotrophic factor (BDNF) brain-derived neurotrophic factor antisense (BDNFAS) Enhancer of zeste homolog 2 (EZH2) hox transcript antisense rna (HOTAIR) epigenetic enzyme rna protein interaction AlphaScreen natural antisense transcript noncoding rna

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Disruption of Visc-2, a Brain-Expressed Conserved Long noncoding rna, Does Not Elicit an Overt Anatomical or Behavioral Phenotype

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CEREBRAL CORTEX 2015年第10期25卷 3572-3585页

作者： Oliver, Peter L. Chodroff, Rebecca A. Gosal, Amrit Edwards, Benjamin Cheung, Amanda F. P. Gomez-Rodriguez, Julio Elliot, Gene Garrett, Lisa J. Lickiss, Tom Szele, Francis Green, Eric D. Molnar, Zoltan Ponting, Chris P. Univ Oxford MRC Funct Genom Unit Oxford OX1 3QX England Univ Oxford Dept Physiol Anat & Genet Oxford OX1 3QX England NHGRI Genome Technol Branch Bethesda MD 20892 USA NHGRI Embryon Stem Cells & Transgen Mouse Core Bethesda MD 20892 USA

Although long noncoding rnas (lncrnas) are proposed to play essential roles in mammalian neurodevelopment, we know little of their functions from their disruption in vivo. Combining evidence for evolutionary constraint and conserved expression data, we previously identified candidate lncrnas that might play important and conserved roles in brain function. Here, we demonstrate that the sequence and neuronal transcription of lncrnas transcribed from the previously uncharacterized Visc locus are conserved across diverse mammals. Consequently, one of these lncrnas, Visc-2, was selected for targeted deletion in the mouse, and knockout animals were subjected to an extremely detailed anatomical and behavioral characterization. Despite a neurodevelopmental expression pattern of Visc-2 that is highly localized to the cortex and sites of neurogenesis, anomalies in neither cytoarchitecture nor neuroproliferation were identified in knockout mice. In addition, no abnormal motor, sensory, anxiety, or cognitive behavioral phenotypes were observed. These results are important because they contribute to a growing body of evidence that lncrna loci contribute on average far less to brain and biological functions than protein-coding loci. A high-throughput knockout program focussing on lncrnas, similar to that currently underway for protein-coding genes, will be required to establish the distribution of their organismal functions.

关键词： evolutionary conservation knockout mouse noncoding rna olfactory bulb subventricular zone

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A Gammaherpesvirus noncoding rna Is Essential for Hematogenous Dissemination and Establishment of Peripheral Latency

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MSPHERE 2016年第2期1卷 e00105-15页

作者： Feldman, Emily R. Kara, Mehmet Oko, Lauren M. Grau, Katrina R. Krueger, Brian J. Zhang, Junjie Feng, Pinghui van Dyk, Linda F. Renne, Rolf Tibbetts, Scott A. Univ Florida Coll Med Dept Mol Genet & Microbiol Gainesville FL 32610 USA Univ Florida Coll Med UF Hlth Canc Ctr Gainesville FL 32610 USA Univ Colorado Sch Med Dept Microbiol & Immunol Aurora CO USA Univ Southern Calif Keck Sch Med Dept Mol Microbiol & Immunol Los Angeles CA USA

Recent intense investigations have uncovered important functions for a diverse array of novel noncoding rna (ncrna) species, including micrornas (mirnas) and long noncoding rnas. Not surprisingly, viruses from multiple families have evolved to encode their own regulatory rnas;however, the specific in vivo functions of these ncrnas are largely unknown. The human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are highly ubiquitous pathogens that are associated with the development of a wide range of malignancies, including Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, and Kaposi's sarcoma. Like EBV and KSHV, murine gammaherpesvirus 68 (MHV68) establishes lifelong latency in B cells and is associated with lymphoproliferative disease and lymphoma. Similar to the EBV-encoded small rna (EBER)-1 and -2, MHV68 encodes eight 200- to 250-nucleotide polymerase III-transcribed ncrnas called TMERs (trna-mirna-encoded rnas), which are highly expressed in latently infected cells and lymphoproliferative disease. To define the in vivo contribution of TMERs to MHV68 biology, we generated a panel of individual TMER mutant viruses. Through comprehensive in vivo analyses, we identified TMER4 as a key mediator of virus dissemination. The TMER4 mutant virus replicated normally in lungs and spread with normal kinetics and distribution to lung-draining lymph nodes, but it was significantly attenuated for infection of circulating blood cells and for latency establishment at peripheral sites. Notably, TMER4 stem-loops but not mirnas were essential for wild-type TMER4 activity. Thus, these findings revealed a crucial mirna-independent function of the TMER4 ncrna in MHV68 hematogenous dissemination and latency establishment. IMPORTANCE noncoding rnas (ncrnas) represent an intriguing and diverse class of molecules that are now recognized for their participation in a wide array of cellular processes. Viruses from multiple familie

关键词： TMER dissemination herpesviruses latency mirna noncoding rna viral pathogenesis

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The cellular landscape of mid-size noncoding rna

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WILEY INTERDISCIPLINARY REVIEWS-rna 2019年第4期10卷 e1530-e1530页

作者： Boivin, Vincent Faucher-Giguere, Laurence Scott, Michelle Abou-Elela, Sherif Univ Sherbrooke Fac Med & Hlth Sci Dept Biochem Sherbrooke PQ Canada Univ Sherbrooke Dept Microbiol & Infect Dis Fac Med & Hlth Sci Sherbrooke PQ Canada

noncoding rna plays an important role in all aspects of the cellular life cycle, from the very basic process of protein synthesis to specialized roles in cell development and differentiation. However, many noncoding rnas remain uncharacterized and the function of most of them remains unknown. Mid-size noncoding rnas (mncrnas), which range in length from 50 to 400 nucleotides, have diverse regulatory functions but share many fundamental characteristics. Most mncrnas are produced from independent promoters although others are produced from the introns of other genes. Many are found in multiple copies in genomes. mncrnas are highly structured and carry many posttranscriptional modifications. Both of these facets dictate their rna-binding protein partners and ultimately their function. mncrnas have already been implicated in translation, catalysis, as guides for rna modification, as spliceosome components and regulatory rna. However, recent studies are adding new mncrna functions including regulation of gene expression and alternative splicing. In this review, we describe the different classes, characteristics and emerging functions of mncrnas and their relative expression patterns. Finally, we provide a portrait of the challenges facing their detection and annotation in databases. This article is categorized under: Regulatory rnas/rnai/Riboswitches > Regulatory rnas rna Structure and Dynamics > rna Structure, Dynamics, and Chemistry rna Structure and Dynamics > Influence of rna Structure in Biological Systems rna Evolution and Genomics > rna and Ribonucleoprotein Evolution

关键词： mid-size noncoding rna noncoding rna snorna snrna trna

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Human trophoblast noncoding rna suppresses CIITA promoter III activity in murine B-lymphocytes

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2003年第3期301卷 718-724页

作者： Geirsson, A Lynch, RJ Paliwal, I Bothwell, ALM Hammond, GL Yale Univ Sch Med Dept Surg New Haven CT 06510 USA Yale Univ Sch Med Immunobiol Sect New Haven CT 06510 USA

Trophoblasts lack expression of all classical MHC antigens. Determination of the mechanism involved could provide insight into selective gene suppression and allograft tolerance. Suppression of class II expression in trophoblasts is secondary to dominant negative trans-acting factors that suppress class II transactivator (CIITA) transcription. We recently described a trophoblast-derived noncoding rna (Tncrna) that suppresses class II expression. Murine B-cells CH27 were stably transfected with Tncrna and analyzed for MHC class II and CIITA expression by FACS and Northern blots. Functional assessment of CIITA promoter III (pIII) was performed by transient transfection of promoter reporter constructs. Methylation of pIII was assessed by Southern blots and FACS. Tncrna suppressed constitutive I-Ak and CIITA expression in murine B-cells CH27. The mechanism involves inhibition of CIITA pIII activity. The mechanism does not involve methylation of the promoter. (C) 2003 Elsevier Science (USA). All rights reserved.

关键词： MHC class II CIITA gene regulation xenograft noncoding rna repressor

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rna G-quadruplex in functional regulation of noncoding rna: Challenges and emerging opportunities

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CELL CHEMICAL BIOLOGY 2024年第1期31卷 53-70页

作者： Sahayasheela, Vinodh J. Sugiyama, Hiroshi Kyoto Univ Grad Sch Sci Dept Chem Kitashirakawa OiwakechoSakyo Ku Kyoto 6068502 Japan Kyoto Univ Inst Integrated Cell Mat Sci WPI iCeMS Yoshida UshinomaechoSakyo Ku Kyoto 6068501 Japan

G-quadruplexes (G4s) are stable, noncanonical structures formed in guanine (G)-rich sequences of DNA/ rna. G4 structures are reported to play a regulatory role in various cellular processes and, recently, a considerable number of studies have attributed new biological functions to these structures, especially in rna. noncoding rna (ncrna), which does not translate into a functional protein, is widely expressed and has been shown to play a key role in shaping cellular activity. There has been growing evidence of G4 formation in several ncrna classes, and it has been identified as a key part for diverse biological functions and physiopathological contexts in neurodegenerative diseases and cancer. This review discusses rna G4s (rG4s) in ncrna, focusing on the molecular mechanism underlying its function. This review also aims to highlight potential and emerging opportunities to identify and target the rG4s in ncrna to understand its function and, ultimately, treat many diseases.

关键词： G-quadruplex noncoding rna gene regulation stress granules

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The long noncoding rna Crnde regulates osteoblast proliferation through the Wnt/β-catenin signaling pathway in mice

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BONE 2020年 130卷 115076-000页

作者： Mulati, Mieradili Kobayashi, Yutaka Takahashi, Akira Numata, Hoashi Saito, Masanori Hiraoka, Yuichi Ochi, Hiroki Sato, Shingo Ezura, Yoichi Yuasa, Masato Hirai, Takashi Yoshii, Toshitaka Okawa, Atsushi Inose, Hiroyuki Tokyo Med & Dent Univ Grad Sch Dept Orthoped Bunkyo Ku 1-5-45 Yushima Tokyo 1138519 Japan TMDU Med Res Inst Lab Mol Neurosci Bunkyo Ku Tokyo 1138510 Japan TMDU Med Res Inst Lab Genome Editing Biomed Res Bunkyo Ku Tokyo 1138510 Japan Tokyo Med & Dent Univ Med Res Inst Dept Mol Pharmacol Tokyo 1138510 Japan

In the past decade, a growing importance has been placed on understanding the significance of long noncoding rnas (lncrnas) in regulating development, metabolism, and homeostasis. Osteoblast proliferation and differentiation are essential elements in skeletal development, bone metabolism, and homeostasis. However, the underlying mechanisms of lncrnas in the process of osteoblast proliferation and differentiation remain largely unknown. Through comprehensive analysis of lncrnas during bone formation, we show that colorectal neoplasia differentially expressed (Crnde), previously viewed as a cancer-related lncrna, is an important regulator of osteoblast proliferation and differentiation. Crnde was found to be expressed in osteoblasts, and its expression was induced by parathyroid hormone. Furthermore, Crnde knockout mice developed a low bone mass phenotype due to impaired osteoblast proliferation and differentiation. Overexpression of Crnde in osteoblasts promoted their proliferation, and conversely, reduced Crnde expression inhibited osteoblast proliferation. Although ablation of Crnde inhibited osteoblast differentiation, overexpression of Crnde restored it. Finally, we provided evidence that Crnde modulates bone formation through Wnt/beta-catenin signaling. Therefore, our data suggest that Crnde is a novel regulator of bone metabolism.

关键词： Parathyroid hormone noncoding rna Osteoporosis Osteoblast Proliferation Wnt signaling

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Long noncoding rna-Directed Epigenetic Regulation of Gene Expression Is Associated With Anxiety-like Behavior in Mice

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BIOLOGICAL PSYCHIATRY 2015年第12期78卷 848-859页

作者： Spadaro, Paola A. Flavell, Charlotte R. Widagdo, Jocelyn Ratnu, Vikram S. Troup, Michael Ragan, Chikako Mattick, John S. Bredy, Timothy W. Univ Queensland Australia Queensland Brain Inst Brisbane Qld Australia St Vincents Hosp Garvan Inst Med Res Darlinghurst NSW 2010 Australia Univ New S Wales St Vincents Clin Sch Kensington NSW 2033 Australia

BACKGROUND: rna-directed regulation of epigenetic processes has recently emerged as an important feature of mammalian differentiation and development. Perturbation of this regulatory system in the brain may contribute to the development of neuropsychiatric disorders. METHODS: rna sequencing was used to identify changes in the experience-dependent expression of long noncoding rnas (lncrnas) within the medial prefrontal cortex of adult mice. Transcripts were validated by real-time quantitative polymerase chain reaction and a candidate lncrna, Gomafu, was selected for further investigation. The functional role of this schizophrenia-related lncrna was explored in vivo by antisense oligonucleotide-mediated gene knockdown in the medial prefrontal cortex, followed by behavioral training and assessment of fear-related anxiety. Long noncoding rna-directed epigenetic regulation of gene expression was investigated by chromatin and rna immunoprecipitation assays. RESULTS: rna sequencing analysis revealed changes in the expression of a significant number of genes related to neural plasticity and stress, as well as the dynamic regulation of lncrnas. In particular, we detected a significant downregulation of Gomafu lncrna. Our results revealed that Gomafu plays a role in mediating anxiety-like behavior and suggest that this may occur through an interaction with a key member of the polycomb repressive complex 1, BMI1, which regulates the expression of the schizophrenia-related gene beta crystallin (Crybb1). We also demonstrated a novel role for Crybb1 in mediating fear-induced anxiety-like behavior. CONCLUSIONS: Experience-dependent expression of lncrnas plays an important role in the epigenetic regulation of adaptive behavior, and the perturbation of Gomafu may be related to anxiety and the development of neuropsychiatric disorders.

关键词： Anxiety Behavior Crybb1 Epigenetics Gomafu noncoding rna

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Landscape of noncoding rna in Prostate Cancer

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TRENDS IN GENETICS 2019年第11期35卷 840-851页

作者： Hua, Junjie T. Chen, Sujun He, Housheng H. Univ Hlth Network Princess Margaret Canc Ctr Toronto ON Canada Univ Toronto Dept Med Biophys Toronto ON Canada

The transcriptome of prostate cancer is highly heterogeneous, with noncoding transcripts being essential players. Long noncoding rnas (lncrnas) and circular rnas (circrnas) are two unique classes of noncoding rna drawing increasing attention. Biologically, they have intriguing properties with important regulatory functions. Clinically, they present as promising biomarkers and therapeutic targets. Recent advancements in technologies have opened up new directions for noncoding rna research, which include rna-protein interaction, rna secondary structure, and spatial transcriptomics. Furthermore, recent work has also evaluated the clinical applications of these noncoding rnas in noninvasive liquid biopsy and rna-based therapies. In this review, we summarize recent findings on lncrnas and circrnas in prostate cancer, discuss their clinical utilities, and highlight these exciting areas of research.

关键词： prostate cancer long noncoding rna circular rna noncoding rna biomarkers therapeutics

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Role of identified noncoding rna in erectile dysfunction

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ANDROLOGIA 2020年第7期52卷 e13596-e13596页

作者： Chen, Sixiang Sun, Xiaoping Wu, Suliu Jiang, Jing Zhu, Chenfeng Xu, Kechen Xu, Keyang Zhejiang Chinese Med Univ Hangzhou Peoples R China Wuyi First Peoples Hosp Wuyi Peoples R China Zhejiang Chinese Med Univ Hangzhou Xixi Hosp Hangzhou Peoples R China

Erectile dysfunction (ED) is a common male sexual dysfunction and is closely related to many risk factors such as age, chronic diseases and mental disorder. Phosphodiesterase type 5 inhibitor (PDE5i) is recommended as the first-line medicine in therapy, but up to 35% of patients fail to this treatment. Unfortunately, the pathogenesis of ED is still poorly understood. Hence, it has reached the state that researchers should seek for new candidate biomarkers or therapeutic targets. Recent studies have reported that noncoding rnas (ncrnas) such as micrornas (mirnas) and long noncoding rnas (lncrnas) are involved in the pathogenesis process of ED, even in stem cell therapy. In this review, we aim to summarise the mechanisms and functions of identified ncrnas that are associated with ED.

关键词： erectile dysfunction long noncoding rna microrna noncoding rna

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