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Expanded Expression Landscape and Prioritization of Circular rnas in Mammals

CELL REPORTS 2019年第12期26卷 3444-+页

作者： Ji, Peifeng Wu, Wanying Chen, Shuai Zheng, Yi Zhou, Lin Zhang, Jinyang Cheng, Hao Yan, Jin Zhang, Shaogeng Yang, Penghui Zhao, Fangqing Chinese Acad Sci Beijing Inst Life Sci Computat Genom Lab Beijing 100101 Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China Beijing 302 Hosp Beijing 100039 Peoples R China Chinese Acad Sci Ctr Excellence Anim Evolut & Genet Kunming 650223 Yunnan Peoples R China

Circular rnas (circrnas) are emerging as essential regulators of various biological and disease processes. To comprehensively understand the diversity of circrnas and prioritize their importance, we present a large-scale study of circrna repertoires from multiple tissues from human, macaque, and mouse. We discovered totals of 104,388, 96,675, and 82,321 circrnas from the three species, respectively, with an average of 72.6% being successfully assembled into full-length transcripts for each species. Using these full-length circrnas, we identified thousands of evolutionarily conserved circrnas that were valuable for functional screening and prioritization. By constructing both species-specific and conserved gene co-expression networks, we inferred circrna functions on a global scale and prioritized promising functional candidates. To illustrate how well-established prior knowledge facilitates to screen functional candidates, we used the circrna co-expression networks to prioritize circrnas that may be involved in liver tumorigenesis and experimentally validated their functions.

关键词： circular rna circrna co-expression network functional prioritization noncoding rna rna-binding protein transcriptome

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Epigenetics: the missing link between genes and psychiatric disorders?

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DIALOGUES IN CLINICAL NEUROSCIENCE 2019年第4期21卷 337-338页

作者： Thibaut, Florence Univ Hosp Cochin Site Tarnier Paris France Paris Univ Fac Med Paris Descartes INSERM Inst Psychiat & NeurosciU1266 Paris France

Most studies describing epigenetic modifications have focused on NA methylation, but fewer studies have focused on histone modifications and noncoding NAs. Chromatin architecture and CCCTC-binding factor represent important noncoding regulatory elements that warrant further investigation in order to improve our understanding of the genomic basis of complex diseases such as psychiatric disorders. (C) 2019, AICH - Servier Group

关键词： epigenetics histones DNA methylation noncoding rna CTCF

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Hatchet ribozyme structure and implications for cleavage mechanism

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2019年第22期116卷 10783-10791页

作者： Zheng, Luqian Falschlunger, Christoph Huang, Kaiyi Mairhofer, Elisabeth Yuan, Shuguang Wang, Juncheng Patel, Dinshaw J. Micura, Ronald Ren, Aiming Zhejiang Univ Life Sci Inst Hangzhou 310058 Zhejiang Peoples R China Leopold Franzens Univ Inst Organ Chem A-6020 Innsbruck Austria Ecole Polytech Fed Lausanne Inst Chem Sci & Engn CH-1015 Lausanne Switzerland Mem Sloan Kettering Canc Ctr Struct Biol Program New York NY 10065 USA Southern Univ Sci & Technol Dept Biol Shenzhen 518055 Guangdong Peoples R China

Small self-cleaving ribozymes catalyze site-specific cleavage of their own phosphodiester backbone with implications for viral genome replication, pre-mrna processing, and alternative splicing. We report on the 2.1-angstrom crystal structure of the hatchet ribozyme product, which adopts a compact pseudosymmetric dimeric scaffold, with each monomer stabilized by long-range interactions involving highly conserved nucleotides brought into close proximity of the scissile phosphate. Strikingly, the catalytic pocket contains a cavity capable of accommodating both the modeled scissile phosphate and its flanking 5' nucleoside. The resulting modeled precatalytic conformation incorporates a splayed-apart alignment at the scissile phosphate, thereby providing structure-based insights into the in-line cleavage mechanism. We identify a guanine lining the catalytic pocket positioned to contribute to cleavage chemistry. The functional relevance of structure-based insights into hatchet ribozyme catalysis is strongly supported by cleavage assays monitoring the impact of selected nucleobase and atom-specific mutations on ribozyme activity.

关键词： hatchet ribozyme cleavage catalysis noncoding rna

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Targeting microrna-134 for seizure control and disease modification in epilepsy

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EBIOMEDICINE 2019年 45卷 646-654页

作者： Morris, Gareth Reschke, Cristina R. Henshall, David C. Royal Coll Surgeons Ireland Dept Physiol & Med Phys Dublin D02 YN77 Ireland Royal Coll Surgeons Ireland FutureNeuro Res Ctr Dublin Ireland

Microrna-134 is a brain-enriched small noncoding rna that has been implicated in diverse neuronal functions, including regulating network excitability. Increased expression of microrna-134 has been reported in several experimental epilepsy models and in resected brain tissue from temporal lobe epilepsy patients. Rodent studies have demonstrated that reducing microrna-134 expression in the brain using antisense oligonucleotides can increase seizure thresholds and attenuate status epilepticus. Critically, inhibition of microrna-134 after status epilepticus can potently reduce the occurrence of spontaneous recurrent seizures. Altered plasma levels of microrna-134 have been reported in epilepsy patients, suggesting microrna-134 may have diagnostic value as a biomarker. This review summarises findings on the cellular functions of microrna-134, as well as the preclinical evidence supporting anti-seizure and disease-modifying effects of targeting microrna-134 in epilepsy. Finally, we draw attention to unanswered questions and some of the challenges and opportunities involved in preclinical development of a microrna-based oligonucleotide treatment for epilepsy. (C) 2019 The Authors. Published by Elsevier B.V.

关键词： Epileptogenesis noncoding rna Hippocampal sclerosis Biomarker rna therapy

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Disruption of the OLE ribonucleoprotein complex causes magnesium toxicity in Bacillus halodurans

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MOLECULAR MICROBIOLOGY 2019年第5期112卷 1552-1563页

作者： Harris, Kimberly A. Odzer, Nicole B. Breaker, Ronald R. Yale Univ Howard Hughes Med Inst New Haven CT 06511 USA Yale Univ Dept Mol Cellular & Dev Biol New Haven CT 06520 USA Yale Univ Dept Mol Biophys & Biochem New Haven CT 06520 USA

OLE rnas represent an unusual class of bacterial noncoding rnas common in Gram-positive anaerobes. The OLE rna of the alkaliphile Bacillus halodurans is highly expressed and naturally interacts with at least two rna-binding proteins called OapA and OapB. The phenotypes of the corresponding knockouts include growth inhibition when exposed to ethanol or other short-chain alcohols or when incubated at modestly reduced temperatures (e.g. 20 degrees C). Intriguingly, the OapA 'PM1' mutant, which carries two amino acid changes to a highly conserved region, yields a dominant-negative phenotype that causes more severe growth defects under these same stress conditions. Herein, we report that the PM1 strain also exhibits extreme sensitivity to elevated Mg2+ concentrations, beginning as low as 2 mM. Suppressor mutants predominantly map to genes for aconitate hydratase and isocitrate dehydrogenase, which are expected to alter cellular citrate concentrations. Citrate reduces the severity of the Mg2+ toxicity phenotype, but neither the genomic mutations nor the addition of citrate to the medium overcomes ethanol toxicity or temperature sensitivity. These findings reveal that OLE rna and its protein partners are involved in biochemical responses under several stress conditions, wherein the unusual sensitivity to Mg2+ can be independently suppressed by specific genomic mutations.

关键词： Mg2+ transport rna-protein interactions ethanol toxicity extremophile membrane protein noncoding rna

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The progression of HMGB1-induced autophagy in cancer biology

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ONCOTARGETS AND THERAPY 2019年 12卷 365-377页

作者： Xu, Tianwei Jiang, Lihua Wang, Zhaoxia Nanjing Med Univ Dept Oncol Affiliated Hosp 2 121 Jiangjiayuan Rd Nanjing 210011 Jiangsu Peoples R China

Autophagy is an important process of cellular degradation and has been proven to contribute to tumorigenesis. High-mobility group box 1 (HMGB1) is an abundant nonhistone protein that has been widely reported to play a central role in the induction of autophagy. In nucleus, HMGB1 upregulates the expression of HSP27 to induce autophagy. In cytoplasm, the Beclin-1/ PI3K-III complex can be activated by HMGB1 to promote autophagy. Extracellular HMGB1 binds to the receptor for advanced glycation end products to induce autophagy. Recent studies have shown that HMGB1-induced autophagy exerts multiple functions in various cancers like proliferation. Moreover, inhibition of HMGB1-induced autophagy can reverse chemoresistance, which is regulated by noncoding rnas such as micrornas and lncrnas. Here, we provide a brief introduction to HMGB1 and HMGB1-induced autophagy in cancer. We also discuss the challenges associated with performing further investigations on this issue. HMGB1-induced autophagy exerts significant functions in cancer and has potential utility for new strategy to reverse drug resistance.

关键词： HMGB1 autophagy cancer noncoding rna drug resistance

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Characterization of novel small rnas (srnas) contributing to the desiccation response of Salmonella enterica serovar Typhimurium

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rna BIOLOGY 2019年第11期16卷 1643-1657页

作者： Barnhill, Emmaline C. Crucello, Aline Houserova, Dominika King, Valeria M. Amin, Shivam V. Roberts, Justin T. Zambrano, Michael E. DeMeis, Jeffrey D. Dahmer, Donavon J. Ijaz, Zara Barchie, Addison A. Watters, Brianna C. Prusak, James E. Dean, Meghan A. Holton, Nathaniel W. Ferreira-Filho, Jaire A. Sant'Ana, Anderson S. Spector, Michael P. Borchert, Glen M. Univ S Alabama Dept Biol Mobile AL 36688 USA Univ Estadual Campinas Dept Food Sci Campinas SP Brazil USA Coll Med Dept Pharmacol Mobile AL USA Univ Calif Berkeley Dept Mol & Cell Biol 229 Stanley Hall Berkeley CA 94720 USA Univ Colorado Sch Med Dept Biochem & Mol Genet Aurora CO USA Univ S Alabama Dept Biomed Sci Mobile AL USA Univ Estadual Campinas Ctr Mol Biol & Genet Engn Campinas SP Brazil

noncoding rna (ncrna) modulation of gene expression has now been ubiquitously observed across all domains of life. An increasingly apparent role of ncrnas is to coordinate changes in gene expressions in response to environmental stress. Salmonella enterica, a common food-born pathogen, is known for its striking ability to survive, adapt, and thrive in various unfavourable environments which makes it a particularly difficult pathogen to eliminate as well as an interesting model in which to study ncrna contributions to cellular stress response. Mounting evidence now suggests that small rnas (srnas) represent key regulators of Salmonella stress adaptation. Approximately 50-500 nucleotides in length, srnas regulate gene expression through complementary base pairing with molecular targets and have recently been suggested to outnumber protein-coding genes in bacteria. In this work, we employ small rna transcriptome sequencing to characterize changes in the srna profiles of Salmonella in response to desiccation. In all, we identify 102 previously annotated srnas significantly differentially expressed during desiccation;and excitingly, 71 novel srnas likewise differentially expressed. Small transcript northern blotting and qRT-PCRs confirm the identities and expressions of several of our novel srnas, and computational analyses indicate the majority are highly conserved and structurally related to characterized srnas. Predicted srna targets include several proteins necessary for desiccation survival and this, in part, suggests a role for desiccation-regulated srnas in this stress response. Furthermore, we find individual knock-outs of two of the novel srnas identified herein, either srna1320429 or srna3981754, significantly impairs the ability of Salmonella to survive desiccation, confirming their involvements (and suggesting the potential involvements of other srnas we identify in this work) in the Salmonella response to desiccation.

关键词： Bacteria desiccation ncrna noncoding rna osmoprotectant prokaryotic ProP Salmonella srna stress transcriptome

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Transcriptomics for Clinical and Experimental Biology Research: Hang on a Seq

Advanced genetics (Hoboken, N.J.)

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Advanced genetics (Hoboken, N.J.) 2023年第2期4卷 2200024页

作者： Tanner Stokes Haoning Howard Cen Philipp Kapranov Iain J Gallagher Andrew A Pitsillides Claude-Henry Volmar William E Kraus James D Johnson Stuart M Phillips Claes Wahlestedt James A Timmons Faculty of Science McMaster University Hamilton L8S 4L8 Canada. Life Sciences Institute University of British Columbia Vancouver V6T 1Z3 Canada. School of Medicine Huaqiao University Xiamen 362021 China. School of Applied Sciences Edinburgh Napier University Edinburgh EH11 4BN UK. Comparative Biomedical Sciences Royal Veterinary College London NW1 0TU UK. Miller School of Medicine University of Miami Miami FL 33136 USA. School of Medicine Duke University Durham NC 27701 USA. William Harvey Research Institute Queen Mary University London London EC1M 6BQ UK. Augur Precision Medicine LTD Stirling FK9 5NF UK.

Sequencing the human genome empowers translational medicine, facilitating transcriptome-wide molecular diagnosis, pathway biology, and drug repositioning. Initially, microarrays are used to study the bulk transcriptome; but now short-read rna sequencing (rna-seq) predominates. Positioned as a superior technology, that makes the discovery of novel transcripts routine, most rna-seq analyses are in fact modeled on the known transcriptome. Limitations of the rna-seq methodology have emerged, while the design of, and the analysis strategies applied to, arrays have matured. An equitable comparison between these technologies is provided, highlighting advantages that modern arrays hold over rna-seq. Array protocols more accurately quantify constitutively expressed protein coding genes across tissue replicates, and are more reliable for studying lower expressed genes. Arrays reveal long noncoding rnas (lncrna) are neither sparsely nor lower expressed than protein coding genes. Heterogeneous coverage of constitutively expressed genes observed with rna-seq, undermines the validity and reproducibility of pathway analyses. The factors driving these observations, many of which are relevant to long-read or single-cell sequencing are discussed. As proposed herein, a reappreciation of bulk transcriptomic methods is required, including wider use of the modern high-density array data-to urgently revise existing anatomical rna reference atlases and assist with more accurate study of lncrnas.

关键词： rna arrays cDNA crna diagnostics drug repurposing lncrna noncoding rna sequencing splicing

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noncoding transcribed ultraconserved region (T-UCR) UC.48+is a novel regulator of high-fat diet induced myocardial ischemia/reperfusion injury

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JOUrnaL OF CELLULAR PHYSIOLOGY 2019年第6期234卷 9849-9861页

作者： Ding, Lu Gong, Chengxin Zhao, Jiani Liu, Xingzi Li, Tao Rao, Shenqiang Wang, Shuo Liu, Yuanyuan Peng, Shanping Xiao, Wen Xiong, Chaopeng Wang, Rumeng Liang, Shangdong Xu, Hong Nanchang Univ Dept Physiol JiangXi Med Coll Nanchang 330006 Jiangxi Peoples R China Nanchang Univ Clin Dept JiangXi Med Coll Nanchang Jiangxi Peoples R China Chest Hosp Jiangxi Prov Dept Sci & Educ Nanchang Jiangxi Peoples R China Nanchang Univ Basic Med Sci JiangXi Med Coll Nanchang Jiangxi Peoples R China Nanchang Univ Dept Pathol Jiangxi Med Coll Nanchang Jiangxi Peoples R China Nanchang Univ Dept Nursing Affliated Hosp 2 Nanchang Jiangxi Peoples R China

Increasing evidence has suggested high-fat diet (HFD) is an independent risk factor for myocardial ischemia/reperfusion (MI/R) injury. Long noncoding rnas (lncrnas) recently attracted much attraction in the study of MI/R injury. However, the functional questions of specific lncrnas in HFD-induced MI/R injury have not been well elucidated. Uc.48+ is a lncrna from a transcribed ultraconserved region (T-UCR) of human, mouse, and rat genomes. Here, we explored the aggravating role of uc.48+and identified purinergic P2X7 receptor (P2X7R) as a downstream regulator of uc.48+ in HFD-induced MI/R vulnerability. We demonstrated uc.48+ expression was upregulated, accompanied by the corresponding upregulation of P2X7R in HFD I/R myocardium and HFD-induced MI/R vulnerability. Overexpression of uc.48+enhanced, whereas silencing of uc.48 + decreased the expression of P2X7R, cardiomyocyte apoptosis, and MI/R injury. The functional relevance of uc.48+ regulated P2X7R expression and the subsequent NF-kappa B signaling to promote cardiomyocyte apoptosis was supported by inhibition of P2X7R with its specific antagonist (A438079) as well as the inhibitor of NF-kappa B signaling (pyrrolidine dithiocarbamate, PDTC) in H9c2 hypoxia/reoxygenation (H/R) cells transfected with pcDNA3.0-uc.48 + plasmid, and rna immunoprecipitation (RIP) suggested uc.48+ could interact with transcription factor Sp1. Importantly, Sp1 inhibitor (mithramycin, MIT) was found to suppress uc.48+ -induced P2X7R expression and the NF-kappa B signaling and cardiomyocyte apoptosis. Our findings provide a potential novel mechanism through which uc.48+ boosts cardiomyocyte apoptosis and MI/R vulnerability to HFD. Thus, uc.48+ is a novel regulator of HFD-induced MI/R injury;targeting uc.48+ may be a novel therapeutic approach of MI/R vulnerability to HFD.

关键词： cardiomyocyte apoptosis high-fat diet ischemia/reperfusion injury noncoding rna

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Establishment and characterization of an anoxia-tolerant cell line, PSU-AL-WS4ONE, derived from an embryo of the annual killifish Austrofundulus limnaeus

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COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY 2019年 232卷 11-22页

作者： Riggs, Claire L. Le, Rosey Kultz, Dietmar Zajic, Daniel Summers, Amanda Alvarez, Luz Podrabsky, Jason E. Portland State Univ Dept Biol POB 751 Portland OR 97207 USA St Louis Univ Dept Biol 1 N Grand Blvd St Louis MO 63103 USA Univ Nevada Sch Life Sci 4505 S Maryland Pkwy Las Vegas NV 89154 USA Univ Calif Davis Dept Anim Sci One Shields Ave Davis CA 95616 USA Villanova Univ Dept Psychol & Brain Sci 800 E Lancaster Ave Villanova PA 19085 USA

Most animal cells rely on aerobic metabolism for survival and are damaged or die within minutes without oxygen. Embryos of the annual killifish Austrofundulus limnaeus, however, survive months without oxygen. Determining how their cells survive without oxygen has the potential to revolutionize our understanding of the cellular mechanisms supporting vertebrate anoxia tolerance and the evolution of such tolerance. Therefore, we aimed to establish and characterize an anoxia-tolerant cell line from A. limnaeus for investigating mechanisms of vertebrate anoxia tolerance. The PSU-AL-WS4ONE cell line of neuroepithelial identity was established from embryonic tissue of A. limnaeus using a tissue explant. The cells can survive for at least 49 d without oxygen or replenishment of growth medium, compared to only 3 d of anoxic survival for two mammalian cell lines. PSU-AL-WS40NE cells accumulate lactate during anoxia, indicating use of common metabolic pathways for anaerobic metabolism. Additionally, they express many of the same small noncoding rnas that are stress-responsive in whole embryos of A. limnaeus and mammalian cells, as well as anoxia-responsive small noncoding rnas derived from the mitochondrial genome (mitosrnas). The establishment of the cell line provides a unique tool for investigating cellular mechanisms of vertebrate anoxia tolerance, and has the potential to transform our understanding of the role of oxidative metabolism in cell biology.

关键词： Anoxia Cell culture Annual killifish noncoding rna

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