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SARS-CoV-2 expresses a microrna-like small rna able to selectively repress host genes

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2021年第52期118卷 e2116668118-e2116668118页

作者： Pawlica, Paulina Yario, Therese A. White, Sylvia Wang, Jianhui Moss, Walter N. Hui, Pei Vinetz, Joseph M. Steitz, Joan A. Yale Univ Dept Mol Biophys & Biochem Sch Med New Haven CT 06536 USA Yale Univ HHMI Sch Med New Haven CT 06536 USA Yale Univ Dept Pathol Sch Med New Haven CT 06536 USA Iowa State Univ Roy J Carver Dept Biochem Biophys & Mol Biol Ames IA 50011 USA Yale Univ Dept Internal Med Sect Infect Dis Sch Med New Haven CT 06520 USA Icahn Sch Med Mt Sinai Dept Microbiol New York NY 10029 USA

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease (COVID-19), continues to be a pressing health concern. In this study, we investigated the impact of SARS-CoV-2 infection on host microrna (mirna) populations in three human lung-derived cell lines, as well as in nasopharyngeal swabs from SARS-CoV-2-infected individuals. We did not detect any major and consistent differences in host mirna levels after SARS-CoV-2 infection. However, we unexpectedly discovered a viral mirna-like small rna, named CoV2-miR-O7a (for SARS-CoV-2 mirna-like ORF7a-derived small rna). Its abundance ranges from low to moderate as compared to host mirnas and it associates with Argonaute proteins-core components of the rna interference pathway. We identify putative targets for CoV2-miRO7a, including Basic Leucine Zipper ATF-Like Transcription Factor 2 (BATF2), which participates in interferon signaling. We demonstrate that CoV2-miR-O7a production relies on cellular machinery, yet is independent of Drosha protein, and is enhanced by the presence of a strong and evolutionarily conserved hairpin formed within the ORF7a sequence.

关键词： micorna SARS-CoV-2 noncoding rna

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An Emerging Role for Enhancer rnas in Brain Disorders

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NEUROMOLECULAR MEDICINE 2024年第1期26卷 7-7页

作者： Patel, Ankit Dharap, Ashutosh Univ S Florida Dept Mol Med Tampa FL 33620 USA USF Byrd Alzheimers Ctr & Res Inst Hlth Neurosci Inst Tampa FL 33620 USA

noncoding DNA undergoes widespread context-dependent transcription to produce noncoding rnas. In recent decades, tremendous advances in genomics and transcriptomics have revealed important regulatory roles for noncoding DNA elements and the rnas that they produce. Enhancers are one such element that are well-established drivers of gene expression changes in response to a variety of factors such as external stimuli, cellular responses, developmental cues, and disease states. They are known to act at long distances, interact with multiple target gene loci simultaneously, synergize with other enhancers, and associate with dynamic chromatin architectures to form a complex regulatory network. Recent advances in enhancer biology have revealed that upon activation, enhancers transcribe long noncoding rnas, known as enhancer rnas (ernas), that have been shown to play important roles in enhancer-mediated gene regulation and chromatin-modifying activities. In the brain, enhancer dysregulation and erna transcription has been reported in numerous disorders from acute injuries to chronic neurodegeneration. Because this is an emerging area, a comprehensive understanding of erna function has not yet been achieved in brain disorders;however, the findings to date have illuminated a role for ernas in activity-driven gene expression and phenotypic outcomes. In this review, we highlight the breadth of the current literature on erna biology in brain health and disease and discuss the challenges as well as focus areas and strategies for future in-depth research on ernas in brain health and disease.

关键词： Enhancer noncoding rna erna lncrna Epigenetics Brain

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Ectopic expression of pericentric HSATII rna results in nuclear rna accumulation, MeCP2 recruitment, and cell division defects

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CHROMOSOMA 2021年第1期130卷 75-90页

作者： Landers, Catherine C. Rabeler, Christina A. Ferrari, Emily K. D'Alessandro, Lia R. Kang, Diana D. Malisa, Jessica Bashir, Safia M. Carone, Dawn M. Univ Connecticut Dept Nutr Sci Storrs CT USA Swarthmore Coll Dept Biol Swarthmore PA 19081 USA Childrens Hosp Philadelphia Philadelphia PA 19104 USA Ohio State Univ Coll Pharm Div Pharmaceut & Pharmacol 500 W 12Th Ave Columbus OH 43210 USA Stanford Univ Sch Med Stanford CA USA

Within the pericentric regions of human chromosomes reside large arrays of tandemly repeated satellite sequences. Expression of the human pericentric satellite HSATII is prevented by extensive heterochromatin silencing in normal cells, yet in many cancer cells, HSATII rna is aberrantly expressed and accumulates in large nuclear foci in cis. Expression and aggregation of HSATII rna in cancer cells is concomitant with recruitment of key chromatin regulatory proteins including methyl-CpG binding protein 2 (MeCP2). While HSATII expression has been observed in a wide variety of cancer cell lines and tissues, the effect of its expression is unknown. We tested the effect of stable expression of HSATII rna within cells that do not normally express HSATII. Ectopic HSATII expression in HeLa and primary fibroblast cells leads to focal accumulation of HSATII rna in cis and triggers the accumulation of MeCP2 onto nuclear HSATII rna bodies. Further, long-term expression of HSATII rna leads to cell division defects including lagging chromosomes, chromatin bridges, and other chromatin defects. Thus, expression of HSATII rna in normal cells phenocopies its nuclear accumulation in cancer cells and allows for the characterization of the cellular events triggered by aberrant expression of pericentric satellite rna.

关键词： noncoding rna Pericentric heterochromatin Chromatin instability Cancer biology Human

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Long and short non-coding rna and radiation response: a review

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TRANSLATIONAL RESEARCH 2021年 233卷 162-179页

作者： May, Jared M. Bylicky, Michelle Chopra, Sunita Coleman, C. Norman Aryankalayil, Molykutty J. NCI Radiat Oncol Branch Ctr Canc Res NIH Bethesda MD USA NCI Radiat Res Program NIH Rockville MD USA

Abbreviations: ASO = anti-sense oligonucleotides;CAD = coronary artery disease;circrna = circular rna;DCA = dicentric chromosome assay;EMT = epithelial-to-mesenchymal transition;Gy = gray (unit);IR = ionizing radiation;lncrna = long noncoding rna;mirna = microrna;mrna = messenger rna;ncrna = noncoding rna;NSCLC = non-small cell lung cancer;PBMC = peripheral blood mononuclear cells;pirna = piwi-interacting rna;rnai = rna interference;ROS = reactive oxygen species;sirna = small interfering rna;shrna = short hairpin rna;snorna = small nucleolar rna;snrna = small nuclear rna;TBI = total body irradiation;trna = transfer rna;UTR = untranslated region Once thought of as arising from "junk DNA," noncoding rnas (ncrnas) have emerged as key molecules in cellular processes and response to stress. From diseases such as cancer, coronary artery disease, and diabetes to the effects of ionizing radiation (IR), ncrnas play important roles in disease progression and as biomarkers of damage. noncoding rnas regulate cellular processes by competitively binding DNA, mrna, proteins, and other ncrnas. Through these interactions, specific ncrnas can modulate the radiosensitivity of cells and serve as diagnostic and prognostic biomarkers of radiation damage, whether from incidental exposure in radiotherapy or in accidental exposure scenarios. Analysis of rna expression after radiation exposure has shown alterations not only in mrnas, but also in ncrnas (primarily mirna, circrna, and lncrna), implying an important role in cellular stress response. Due to their abundance and stability in serum and other biofluids, ncrnas also have great potential as minimally invasive biomarkers with advantages over current biodosimetry methods. Several studies have examined changes in ncrna expression profiles in response to IR and other forms of oxidative stress. Furthermore, some studies have reported modulation of radiosensitivity by altering expression levels of these ncrnas. This review discusses the rol

关键词： ASO anti-sense oligonucleotides CAD coronary artery disease circrna circular rna DCA dicentric chromosome assay EMT epithelial-to-mesenchymal transition Gy gray (unit) IR ionizing radiation lncrna long noncoding rna mirna microrna mrna messenger rna ncrna noncoding rna NSCLC non-small cell lung cancer PBMC peripheral blood mononuclear cells pirna piwi-interacting rna rnai rna interference ROS reactive oxygen species sirna small interfering rna shrna short hairpin rna snorna small nucleolar rna snrna small nuclear rna TBI total body irradiation trna transfer rna UTR untranslated region

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Biogenesis, Functions, and Cancer Relationships of a Specific Circular rna: CircFoxo3

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RUSSIAN JOUrnaL OF BIOORGANIC CHEMISTRY 2021年第6期47卷 1190-1200页

作者： Zhang, Cai Li, Bin Huang, Yong Gao, Shiyang Gao, Xiaochan Henan Univ Sci & Technol Coll Anim Sci & Technol Luoyang 471023 Peoples R China

Circrnas are a new type of endogenous ncrnas, and are characterized by a covalently closed continuous loop structure having no 5 ' terminal cap and 3 ' ends. With the progression of rna sequencing and the rapid growth of bioinformatics analyses, circrnas were identified across a broad range of organisms from eukaryotes, prokaryotes, microbes and viruses. Growing evidence suggests that circrnas are found to impact several pathological and physiological processes as either tumor suppressor genes or oncogenes, and play multiple biological functions in both occurrence and development of many diseases, especially in cancers. A recently identified a circrna, circFoxo3, were found to be closely associated with different cancers. Therefore, it seems that further research on circFoxo3 could facilitate the diagnosis and treatment of cancers. The current review summarized the characteristics, biogenesis and function of circrnas and focused on the latest advance concerning the roles of circFoxo3 research and their potential to be used as a promising therapeutic targets and diagnostic biomarkers.

关键词： noncoding rna circFoxo3 biogenesis function diseases cancers

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The NLRP3 inflammasome: Multiple activation pathways and its role in primary cells during ventricular remodeling

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JOUrnaL OF CELLULAR PHYSIOLOGY 2021年第8期236卷 5547-5563页

作者： Yan, Zhipeng Qi, Zhongwen Yang, Xiaoya Ji, Nan Wang, Yueyao Shi, Qi Li, Meng Zhang, Junping Zhu, Yaping Tianjin Univ Tradit Chinese Med Dept Cardiol Teaching Hosp 1 88 Changling Rd Tianjin 300381 Peoples R China Natl Clin Res Ctr Chinese Med Acupuncture & Moxib Tianjin Peoples R China

Inflammasomes are a group of multiprotein signaling complexes located in the cytoplasm. Several inflammasomes have been identified, including NLRP1, NLRP2, NLRP3, AIM2, and NLRC4. Among them, NLRP3 was investigated in most detail, and it was reported that it can be activated by many different stimuli. Increased NLRP3 protein expression and inflammasome assembly lead to caspase-1 mediated maturation and release of IL-1 beta, which triggers inflammation and pyroptosis. The activation of the NLRP3 inflammasome has been widely reported in studies of tumors and neurological diseases, but relatively few studies on the cardiovascular system. Ventricular remodeling (VR) is an important factor contributing to heart failure (HF) after myocardial infarction (MI). Consequently, delaying VR is of great significance for improving heart function. Studies have shown that the NLRP3 inflammasome plays an essential role in the process of VR. Here, we reviewed the latest studies on the activation pathway of the NLRP3 inflammasome, focusing on the effects of the NLRP3 inflammasome in primary cells during VR, and finally discuss future research directions in this field.

关键词： cardiomyocytes NLRP3 inflammasome noncoding rna vascular endothelial cells ventricular remodeling

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The effect of LINC9137 targeting miR-140-3p-NKAIN3 signal axis on the development of goose testis sertoli cells

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POULTRY SCIENCE 2024年第6期103卷 103724页

作者： Wu, Yingping Lu, Lizhi Li, Haiying Chen, Li Gu, Tiantian Zhao, Xiaoyu Yao, Yingying Li, Jiahui Xinjiang Agr Univ Coll Anim Sci Urumqi 830000 Peoples R China Zhejiang Acad Agr Sci Inst Anim Husb & Vet Med Hangzhou 310021 Peoples R China

Sertoli cells (SC) are a type of important cells in the testes, which can provide transport proteins, regulatory proteins, growth factors, and other cytokines for the spermatogenic process. They participate in the regulation of the maturation and differentiation of spermatogenic cells and play an important supporting role in the migration, proliferation, and differentiation of germ cells at all levels in the testes. Previous studies found differential expression of LINC9137, miR-140-3p, and Sodium/Potassium Transporting ATPase Interacting 3 (NKAIN3) genesin high and low sperm motility goose testicular tissues. This study investigated the effects of the LINC9137-miR-140-3p-NKAIN3 signal axis on the proliferation and apoptosis of goose testicular sertoli cells at the cellular level, respectively. The results showed that through acridine orange staining, oil red O staining, Alkaline phosphatase (AKP) staining, and RT qPCR assay, it was comprehensively identified that the cultured testicular sertoli cells were purified in vitro. Through the dual luciferase activity detection test, it was found that LINC9137 has a targeted binding site with miR-140-3p and NKAIN3. In addition, this study found that overexpression of miR-140-3p significantly inhibited the expression of LINC9137 and NKAIN3 in sertoli cells, and their expression was significantly increased when miR-140-3p was interfered with. By measuring cell proliferation activity and apoptosis related gene expression, it was found that overexpression of LINC9137 decreased cell proliferation activity (P > 0.05), while the expression level of apoptosis factor Bcl2 Associated X Protein (Bax)/B-cell lymphoma-2 (Bcl2) increased (P > 0.05). On the contrary, when interfering with LINC9137, the cell proliferation activity of sertoli cells was significantly increased (P < 0.01), and the expression level of apoptosis factor Bax/Bcl2 was significantly reduced (P < 0.05);The effect of miR-140-3p on the proliferation and apoptosis of

关键词： goose testicular development sperm motility noncoding rna Cerna

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Bioinformatic prediction of proteins relevant to functions of the bacterial OLE ribonucleoprotein complex

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MSPHERE 2024年第6期9卷 e0015924页

作者： Fernando, Chrishan M. Breaker, Ronald R. Yale Univ Dept Mol Biophys & Biochem New Haven CT 06520 USA Yale Univ Dept Mol Cellular & Dev Biol New Haven CT 06520 USA Yale Univ Howard Hughes Med Inst New Haven CT 06520 USA

OLE (ornate, large, extremophilic) rnas are members of a noncoding rna class present in many Gram-positive, extremophilic bacteria. The large size, complex structure, and extensive sequence conservation of OLE rnas are characteristics consistent with the hypothesis that they likely function as ribozymes. The OLE rna representative from Halalkalibacterium halodurans is known to localize to the phospholipid membrane and requires at least three essential protein partners: OapA, OapB, and OapC. However, the precise biochemical functions of this unusual ribonucleoprotein (RNP) complex remain unknown. Genetic disruption of OLE rna or its partners revealed that the complex is beneficial under diverse stress conditions. To search for additional links between OLE rna and other cellular components, we used phylogenetic profiling to identify proteins that are either correlated or anticorrelated with the presence of OLE rna in various bacterial species. This analysis revealed strong correlations between the essential protein-binding partners of OLE rna and organisms that carry the ole gene. Similarly, proteins involved in sporulation are correlated, suggesting a potential role for the OLE RNP complex in spore formation. Intriguingly, the Mg2+ transporter MpfA is strongly anticorrelated with OLE rna. Evidence indicates that MpfA is structurally related to OapA and therefore MpfA may serve as a functional replacement for some contributions otherwise performed by the OLE RNP complex in species that lack this device. Indeed, OLE rnas might represent an ancient rna class that enabled primitive organisms to sense and respond to major cellular stresses. IMPORTANCE OLE (ornate, large, extremophilic) rnas were first reported nearly 20 years ago, and they represent one of the largest and most intricately folded noncoding rna classes whose biochemical function remains to be established. Other rnas with similar size, structural complexity, and extent of sequence conservation have proven to

关键词： bTOR comparative genomics MpfA noncoding rna phylogenetics rna World

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A guide to rna structure analysis and rna-targeting methods

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FEBS JOUrnaL 2024年第0期 2024 Dec 24页

作者： Aguilar, Rodrigo Mardones, Constanza Moreno, Adrian A. Cepeda-Plaza, Marjorie Univ Andres Bello Inst Biomed Sci ICB Fac Med Echaurren 183 Santiago 8370071 Chile Univ Andres Bello Inst Biomed Sci ICB Fac Life Sci Echaurren 183 Santiago 8370071 Chile Univ Andres Bello Fac Ciencias Vida Ctr Biotecnol Vegetal Santiago Chile Univ Andres Bello Chem Sci Dept Santiago Chile

rnas are increasingly recognized as promising therapeutic targets, susceptible to modulation by strategies that include targeting with small molecules, antisense oligonucleotides, deoxyribozymes (DNAzymes), or CRISPR/Cas13. However, while drug development for proteins follows well-established paths for rational design based on the accurate knowledge of their three-dimensional structure, rna-targeting strategies are challenging since comprehensive rna structures are yet scarce and challenging to acquire. Numerous methods have been developed to elucidate the secondary and three-dimensional structure of rnas, including X-ray crystallography, cryo-electron microscopy, nuclear magnetic resonance, SHAPE, DMS, and bioinformatic methods, yet they have often revealed flexible transcripts and co-existing populations rather than single-defined structures. Thus, researchers aiming to target rnas face a critical decision: whether to acquire the detailed structure of transcripts in advance or to adopt phenotypic screens or sequence-based approaches that are independent of the structure. Still, even in strategies that seem to rely only on the nucleotide sequence (like the design of antisense oligonucleotides), researchers may need information about the accessibility of the compounds to the folded rna molecule. In this concise guide, we provide an overview for researchers interested in targeting rnas: We start by revisiting current methodologies for defining secondary or three-dimensional rna structure and then we explore rna-targeting strategies that may or may not require an in-depth knowledge of rna structure. We envision that complementary approaches may expedite the development of rna-targeting molecules to combat disease.

关键词： noncoding rna rna rna structure rna targeting

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Regulatory Network of Two Tumor-Suppressive noncoding rnas Interferes with the Growth and Metastasis of Renal Cell Carcinoma

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MOLECULAR THERAPY-NUCLEIC ACIDS 2019年 16卷 554-565页

作者： Zhou, Hui Tang, Kun Liu, Haoran Zeng, Jin Li, Heng Yan, Libin Hu, Junhui Guan, Wei Chen, Ke Xu, Hua Ye, Zhangqun Huazhong Univ Sci & Technol Tongji Hosp Tongji Med Coll Dept Urol Wuhan 430030 Hubei Peoples R China Hubei Inst Urol Wuhan 430030 Hubei Peoples R China

noncoding rnas (ncrnas) such as micrornas (mirnas) and long ncrnas (Incrnas) have been shown to function as pivotal regulators in the carcinogenesis of renal cell carcinoma (RCC). However, the functions and underlying mechanisms of most ncrnas in RCC are still elusive, and the crosstalks of different layers of ncrnas are seldom reported. Here we showed that miR-124 and maternally expressed gene 3 (MEG3) were both significantly reduced in RCC, and combined expression of miR-124 and MEG3 emerged as an independent prognostic factor in our RCC cohort. Overexpression of miR-124 or MEG3 inhibited cell proliferation, migration, and invasion in vitro, and restrained tumor growth in vivo. EZH2 knockdown induced the epigenetic silencing of miR-124 and MEG3 expression by H3K27me3. Besides, miR-124 directly targeted the TET1 transcript, and then the interaction resulted in the upregulation of MEG3. Furthermore, we demonstrated that MEG3 induced p53 protein accumulation, whereas p53 was a positive transcriptional regulator of the miR-124. In addition, tumor-suppressive PTPN11 was identified as a direct target of miR-124, as well as the MEG3- and p53-regulated gene. Our study identifies three crosstalks between miR-124 and MEG3, which provide a plausible link for these two ncrnas in RCC. Both ncrnas exert important antitumor effects in RCC path-ogenesis and might serve as prognostic biomarkers and molecular therapeutic targets.

关键词： EZH2 MEG3 PTPN11 methylation miR-124 noncoding rna p53 renal cell carcinoma

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