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An Evaluation of Function of Multicopy noncoding rnas in Mammals Using ENCODE/FANTOM Data and Comparative Genomics

MOLECULAR BIOLOGY AND EVOLUTION 2018年第6期35卷 1451-1462页

作者： Hoeppner, Marc P. Denisenko, Elena Gardner, Paul P. Schmeier, Sebastian Poole, Anthony M. Christian Albrechts Univ Kiel Inst Clin Mol Biol Kiel Germany Massey Univ Inst Nat & Math Sci Auckland New Zealand Univ Canterbury Sch Biol Sci Biomol Interact Ctr Christchurch New Zealand Univ Auckland Bioinformat Inst Sch Biol Sci Auckland New Zealand

Mammalian diversification has coincided with a rapid proliferation of various types of noncoding rnas, including members of both snrnas and snornas. The significance of this expansion however remains obscure. While some ncrna copy-number expansions have been linked to functionally tractable effects, such events may equally likely be neutral, perhaps as a result of random retrotransposition. Hindering progress in our understanding of such observations is the difficulty in establishing function for the diverse features that have been identified in our own genome. Projects such as ENCODE and FANTOM have revealed a hidden world of genomic expression patterns, as well as a host of other potential indicators of biological function. However, such projects have been criticized, particularly from practitioners in the field of molecular evolution, where many suspect these data provide limited insight into biological function. The molecular evolution community has largely taken a skeptical view, thus it is important to establish tests of function. We use a range of data, including data drawn from ENCODE and FANTOM, to examine the case for function for the recent copy number expansion inmammals of six evolutionarily ancient rna families involved in splicing and rrna maturation. We use several criteria to assess evidence for function: conservation of sequence and structure, genomic synteny, evidence for transposition, and evidence for species-specific expression. Applying these criteria, we find that only aminority of loci show strong evidence for function and that, for the majority, we cannot reject the null hypothesis of no function.

关键词： evolution noncoding rna bioinformatics

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The Role of noncoding rnas in Osteogenic Differentiation of Human Periodontal Ligament Stem Cells

Craniomaxillofacial Research & Innovation

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Craniomaxillofacial Research & Innovation 2021年 6卷

作者： Paras Ahmad Martin J. Stoddart Elena Della Bella AO Research Institute Davos Davos Platz Switzerland AO Research Institute Davos Davos Platz SwitzerlandDepartment of Oral and Maxillofacial Surgery Faculty of Medicine Medical Center-University of Freiburg University of Freiburg Freiburg im Breisgau Germany

Chronic inflammatory diseases, including periodontitis, are the most common causes of bone tissue destruction. Periodontitis often leads to loss of connective tissue homeostasis and reduced alveolar bone levels. Human periodontal ligament stem cells (PDLSCs), a population of multipotent stem cells derived from periodontal ligament tissues, are considered as candidate cells for the regeneration of alveolar bone and periodontal tissues. Periodontitis impairs the osteogenic differentiation of human PDLSCs. noncoding rnas (ncrnas), including long noncoding rna (lncrna), microrna (mirna), and circular rna (circrna), have been proposed as vital regulators influencing several differentiation processes including bone regeneration. Still, the molecular mechanisms of ncrnas regulating osteogenic differentiation of human PDLSCs remain poorly understood. Exploring the influence of ncrnas in the process of osteogenic differentiation of human PDLSCs may provide novel therapeutic strategies for tissue regeneration as the regeneration of the lost periodontium is the ultimate goal of periodontal therapy.

关键词： PDLSC periodontitis noncoding rna mirna lncrna circrna

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Serum Expression of Seven Micrornas in Chronic Lymphocytic Leukemia Patients

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JOUrnaL OF BLOOD MEDICINE 2020年 11卷 97-102页

作者： Farzadfard, Ehsan Kalantari, Tahereh Tamaddon, Gholamhossein Shiraz Univ Med Sci Sch Paramed Sci Shiraz Iran Shiraz Univ Med Sci Sch Paramed Sci Dept Med Biotechnol Shiraz Iran Shiraz Univ Med Sci Sch Paramed Sci Dept Clin Lab Sci Shiraz Iran Shiraz Univ Med Sci Sci & Technol Res Ctr Sch Paramed Sci Diagnost Lab Shiraz Iran

Purpose: Micrornas are small single-strand noncoding rnas that can be deregulated in a variety of cancers. Over the past few years, multiple markers have been discovered in chronic lymphocytic leukemia (CLL). Among these, mirnas seem to have important roles in the pathogenesis of CLL. The development and validation of mirna-expression patterns as bio-markers should have a significant impact in cancer diagnosis, therapeutic success, and increasing the life expectancy of patients. In this study, to specify the utility of circulatory mirna expression as noninvasive and useful biomarkers for CLL, we analyzed the dysregulation of seven mirnas: miR30d, miR25-3p, miR19a-3p, miR133b, miR451a, miR145, and miR144 in CLL-patient sera. Methods: Thirty untreated patients with flow-cytometry confirmation of CLL were chosen. Serum samples were collected from 30 newly diagnosed CLL patients. Fifteen healthy samples were taken for comparison as controls. rnawas extracted using Trizol. rna from CLL patient specimens was compared to controls with real-time PCR. Results: Seven mirnas were differently expressed between CLL and normal specimens using the comparative 2(-Delta Delta Ct) method. mirnas 133b, 25-3p, 451a, 145, 19a-3p, and 144 were overexpressed in sera obtained from CLL patients, and mirna-30d was under-expressed in patient samples. Among these seven mirnas, miR19a-3p and miR25-3p showed the most deregulation in CLL patients. Conclusion: Real-time PCR is an applied means to perform high-throughput investigation of serum-rna samples. We assessed the expression of seven mirnas in CLL patients by this method. The results demonstrated that the use of mirna-expression profiling may have an impressive role in the diagnosis of CLL. In addition, mirna 19a-3p and 25-3p are known oncogenes with therapeutic and potential biomarkers.

关键词： chronic lymphocytic leukemia circulatory micrornas noncoding rna real-time PCR

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Gender-Specific Effects of Selection for Drinking in the Dark on the Network Roles of Coding and noncoding rnas

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ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH 2018年第8期42卷 1454-1465页

作者： Iancu, Ovidiu Dan Colville, Alex M. Wilmot, Beth Searles, Robert Darakjian, Priscila Zheng, Christina McWeeney, Shannon Kawane, Sunita Crabbe, John C. Metten, Pamela Oberbeck, Denesa Hitzemann, Robert Oregon Hlth & Sci Univ Dept Behav Neurosci Portland OR 97239 USA Oregon Hlth & Sci Univ Integrated Genom Lab Portland OR 97201 USA Oregon Hlth & Sci Univ Dept Med Informat & Clin Epidemiol Portland OR 97201 USA Oregon Hlth & Sci Univ Knight Canc Inst Portland OR 97201 USA VA Portland Hlth Care Syst Portland OR USA

BackgroundTranscriptional differences between heterogeneous stock mice and high drinking-in-the-dark selected mouse lines have previously been described based on microarray technology coupled with network-based analysis. The network changes were reproducible in 2 independent selections and largely confined to 2 distinct network modules;in contrast, differential expression appeared more specific to each selected line. This study extends these results by utilizing rna-Seq technology, allowing evaluation of the relationship between genetic risk and transcription of noncoding rna (ncrna);we additionally evaluate sex-specific transcriptional effects of selection. MethodsNaive mice (N=24/group and sex) were utilized for gene expression analysis in the ventral striatum;the transcriptome was sequenced with the Illumina HiSeq platform. Differential gene expression and the weighted gene co-expression network analysis were implemented largely as described elsewhere, resulting in the identification of genes that change expression level or (co)variance structure. ResultsAcross both sexes, we detect selection effects on the extracellular matrix and synaptic signaling, although the identity of individual genes varies. A majority of nc rnas cluster in a single module of relatively low density in both the male and female network. The most strongly differentially expressed transcript in both sexes was Gm22513, a small nuclear rna with unknown function. Associated with selection, we also found a number of network hubs that change edge strength and connectivity. At the individual gene level, there are many sex-specific effects;however, at the annotation level, results are more concordant. ConclusionsIn addition to demonstrating sex-specific effects of selection on the transcriptome, the data point to the involvement of extracellular matrix genes as being associated with the binge drinking phenotype.

关键词： Alcohol Drinking in the Dark Binge Mouse Differential Network Analysis noncoding rna Selective Breeding Sex-Specific Effects

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The role of noncoding rnas in regulating epithelial responses in COPD

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AMERICAN JOUrnaL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY 2018年第2期315卷 L184-L192页

作者： Chen, Yifan Thomas, Paul S. Kumar, Rakesh K. Herbert, Cristan Univ New South Wales Australia Sch Med Sci Dept Pathol Sydney NSW 2052 Australia Prince Wales Hosp Dept Resp Med Sydney NSW Australia

Chronic obstructive pulmonary disease (COPD), one of the leading causes of death in the world, is a chronic inflammatory disease of the airways usually caused by long-term exposure to inhaled irritants. Airway epithelial cells (AECs) play a key role in initializing COPD and driving the exacerbation of this disease through the release of various cytokines. This AEC-derived cytokine response is tightly regulated possibly through the regulatory effects of noncoding rnas (ncrnas). Although the importance of ncrnas in pulmonary diseases has been increasingly realized, little is known about the role of ncrna in the regulation of inflammatory responses in COPD. This review outlines the features of AEC-derived cytokine responses in COPD and how ncrnas regulate these inflammatory responses.

关键词： COPD cytokines epithelial cell noncoding rna

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rna-Mediated Feedback Control of Transcriptional Condensates

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CELL 2021年第1期184卷 207-+页

作者： Henninger, Jonathan E. Oksuz, Ozgur Shrinivas, Krishna Sagi, Ido LeRoy, Gary Zheng, Ming M. Andrews, J. Owen Zamudio, Alicia, V Lazaris, Charalampos Hannett, Nancy M. Lee, Tong Ihn Sharp, Phillip A. Cisse, Ibrahim I. Chakraborty, Arup K. Young, Richard A. Whitehead Inst Biomed Res Cambridge MA 02142 USA MIT Dept Chem Engn Cambridge MA 02139 USA MIT Dept Biol 77 Massachusetts Ave Cambridge MA 02139 USA MIT Dept Phys Cambridge MA 02139 USA MIT Dept Chem Cambridge MA 02139 USA MIT Inst Med Engn & Sci 77 Massachusetts Ave Cambridge MA 02139 USA MIT Koch Inst Integrat Canc Res 77 Massachusetts Ave Cambridge MA 02139 USA Harvard Univ NSF Simons Ctr Math & Stat Anal Biol Cambridge MA 02138 USA NYU Sch Med Howard Hughes Med Inst New York NY 10016 USA NYU Sch Med Dept Biochem & Mol Pharmacol New York NY 10016 USA Broad Inst MIT & Harvard Klarman Cell Observ Cambridge MA 02142 USA MIT & Harvard Univ Ragon Inst Massachusetts Gen Hosp Cambridge MA 02139 USA

Regulation of biological processes typically incorporates mechanisms that initiate and terminate the process and, where understood, these mechanisms often involve feedback control. Regulation of transcription is a fundamental cellular process where the mechanisms involved in initiation have been studied extensively, but those involved in arresting the process are poorly understood. Modeling of the potential roles of rna in transcriptional control suggested a non-equilibrium feedback control mechanism where low levels of rna promote condensates formed by electrostatic interactions whereas relatively high levels promote dissolution of these condensates. Evidence from in vitro and in vivo experiments support a model where rnas produced during early steps in transcription initiation stimulate condensate formation, whereas the burst of rnas produced during elongation stimulate condensate dissolution. We propose that transcriptional regulation incorporates a feedback mechanism whereby transcribed rnas initially stimulate but then ultimately arrest the process.

关键词： transcription non-equilibrium rna feedback phase separation mediator complex coacervates transcriptional condensates noncoding rna enhancer

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Long noncoding rnas in Atherosclerosis JACC Review Topic of the Week

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JOUrnaL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2018年第19期72卷 2380-2390页

作者： Zhang, Zhengyi Salisbury, David Sallam, Tamer Univ Calif Los Angeles Div Cardiol Dept Med Los Angeles CA USA Univ Calif Los Angeles Inst Mol Biol Los Angeles CA 90024 USA

Atherosclerosis is a complex and chronic disease characterized by lipid deposition in the vessel wall that leads to an inflammatory and proliferative cascade involving smooth muscle, endothelial, and immune cells. Despite substantial improvements in our understanding of mechanisms contributing to atherosclerosis and overall reduction in cardiovascular mortality, the absolute disease burden remains substantially high. The recent discovery of a new group of mediators known as long noncoding ribonucleic acids (lncrnas) offers a unique opportunity for the development of novel diagnostic and therapeutic tools in atherothrombotic disease. A number of studies suggest that lncrnas are important mediators in health and disease, and rapidly accumulating evidence implicates lncrnas in regulatory circuits controlling atherosclerosis. In this review, the authors outline important contributions of lncrnas to atherosclerosis and its associated risk factors, including hypercholesterolemia, diabetes, hypertension, and obesity. (c) 2018 by the American College of Cardiology Foundation.

关键词： arteriosclerosis bioinformatics genetic knockout models genetics noncoding rna

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Recent trends on the role of epigenomics, metabolomics and noncoding rnas in rationalizing mood stabilizing treatment

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PHARMACOGENOMICS 2018年第2期19卷 129-143页

作者： Pisanu, Claudia Katsila, Theodora Patrinos, George P. Squassina, Alessio Univ Cagliari Sect Neurosci & Clin Pharmacol Dept Biomed Sci Cagliari Italy Uppsala Univ Unit Funct Pharmacol Dept Neurosci Uppsala Sweden Univ Patras Sch Hlth Sci Dept Pharm Patras Greece United Arab Emirates Univ Coll Med & Hlth Sci Dept Pathol Al Ain U Arab Emirates Dalhousie Univ Dept Psychiat Halifax NS Canada

y Mood stabilizers are the cornerstone in treatment of mood disorders, but their use is characterized by high interindividual variability. This feature has stimulated intensive research to identify predictive biomarkers of response and disentangle the molecular bases of their clinical efficacy. Nevertheless, findings from studies conducted so far have only explained a small proportion of the observed variability, suggesting that factors other than DNA variants could be involved. A growing body of research has been focusing on the role of epigenetics and metabolomics in response to mood stabilizers, especially lithium salts. Studies from these approaches have provided new insights into the molecular networks and processes involved in the mechanism of action of mood stabilizers, promoting a systems-level multiomics synergy. In this article, we reviewed the literature investigating the involvement of epigenetic mechanisms, noncoding rnas and metabolomic modifications in bipolar disorder and the mechanism of action and clinical efficacy of mood stabilizers.

关键词： carbamazepine epigenetics lithium metabolomics mood stabilizers noncoding rna valproate

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Sex-based erna expression and function in ischemic stroke

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NEUROCHEMISTRY INTErnaTIONAL 2021年 150卷 105149-105149页

作者： Ruiz, Diandra Bhattarai, Sunil Dharap, Ashutosh HackensackMeridian Hlth JFK Univ Med Ctr JFK Neurosci Inst Lab Stroke Res & Noncoding RNA Biol Edison NJ 08820 USA Hackensack Meridian Sch Med Dept Neurol Nutley NJ 07110 USA

Enhancer-derived rnas (ernas) are a new class of long noncoding rna that have roles in modulating enhancermediated gene transcription, which ultimately influences phenotypic outcomes. We recently published the first study mapping genome-wide erna expression in the male mouse cortex during ischemic stroke and identified 77 ernas that were significantly altered following a 1 h middle cerebral artery occlusion (MCAO) and 6 h of reperfusion, as compared to sham controls. Knockdown of one such stroke-induced erna - erna_06347 resulted in significantly larger infarcts, demonstrating a role for erna_06347 in modulating the post-stroke pathophysiology in males. In the current study, we applied quantitative real-time PCR to evaluate whether the 77 ernas identified in the male cortex also show altered expression in the post-stroke female cortex. Using age-matched and time-matched female mice, we found that only a subset of the 77 ernas were detected in the post-stroke female cortex. Of these, only a small fraction showed similar temporal expression characteristics as males, including erna_06347 which was highly induced in both sexes. Knockdown of erna_06347 in the female cortex resulted in significantly increased infarct volumes that were closely matched to those in males, indicating that erna_06347 modulates the post-stroke pathophysiology similarly in males and females. This suggests a common underlying role for erna_06347 in the two sexes. Overall, this is the first study to evaluate erna expression and perturbation in the female cortex during stroke, and present a comparative analysis between males and females. Our findings show that ernas have sex-dependent and sex-independent expression patterns that may be of significance to the pathophysiological responses to stroke in the two sexes.

关键词： Ischemic stroke noncoding rna erna Sex differences Mouse

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Microrna-Mediated Regulation of Initial Host Responses in a Symbiotic Organ

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MSYSTEMS 2021年第3期6卷 e00081-21页

作者： Moriano-Gutierrez, Silvia Ruby, Edward G. McFall-Ngai, Margaret J. Univ Hawaii Manoa Pacific Biosci Res Ctr Honolulu HI 96822 USA Univ Lausanne Dept Fundamental Microbiol Lausanne Switzerland

One of the most important events in an animal's life history is the initial colonization by its microbial symbionts, yet little is known about this event's immediate impacts on the extent of host gene expression or the molecular mechanisms controlling it. Micrornas (mirnas) are short, noncoding rnas that bind to target mrnas, rapidly shaping gene expression by posttranscriptional control of mrna translation and decay. Here, we show that, in the experimentally tractable binary squid-vibrio symbiosis, colonization of the light organ induces extensive changes in the mirna transcriptome. Examination of the squid genome revealed the presence of evolutionarily conserved genes encoding elements essential for the production and processing of mirnas. At 24 h postcolonization, 215 host mirnas were detected in the light organ, 26 of which were differentially expressed in response to the symbionts. A functional enrichment analysis of genes potentially targeted by downregulation of certain mirnas at the initiation of symbiosis revealed two major gene ontology (GO) term categories, neurodevelopment and tissue remodeling. This symbiont-induced downregulation is predicted to promote these activities in host tissues and is consistent with the well-described tissue remodeling that occurs at the onset of the association. Conversely, predicted targets of upregulated mirnas, including the production of mucus, are consistent with attenuation of immune responses by symbiosis. Taken together, our data provide evidence that, at the onset of symbiosis, host mirnas in the light organ drive alterations in gene expression that (i) orchestrate the symbiont-induced development of host tissues, and (ii) facilitate the partnership by dampening the immune response. IMPORTANCE Animals often acquire their microbiome from the environment at each generation, making the initial interaction of the partners a critical event in the establishment and development of a stable, healthy symbiosis. However, the m

关键词： noncoding rna symbiosis onset Euprymna scolopes Vibrio fischeri development immune response developmental biology

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