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Origins and Evolution of Microrna Genes in Drosophila Species

GENOME BIOLOGY AND EVOLUTION 2010年第0期2卷 180-189页

作者： Nozawa, Masafumi Miura, Sayaka Nei, Masatoshi Penn State Univ Inst Mol Evolutionary Genet University Pk PA 16802 USA Penn State Univ Dept Biol University Pk PA 16802 USA

Micrornas (miRs) regulate gene expression at the posttranscriptional level. To obtain some insights into the origins and evolutionary patterns of miR genes, we have identified miR genes in the genomes of 12 Drosophila species by bioinformatics approaches and examined their evolutionary changes. The results showed that the extant and ancestral Drosophila species had more than 100 miR genes and frequent gains and losses of miR genes have occurred during evolution. Although many miR genes appear to have originated from random hairpin structures in intronic or intergenic regions, duplication of miR genes has also contributed to the generation of new miR genes. Estimating the rate of nucleotide substitution of miR genes, we have found that newly arisen miR genes have a substitution rate similar to that of synonymous nucleotide sites in protein-coding genes and evolve almost neutrally. This suggests that most new miR genes have not acquired any important function and would become inactive. By contrast, old miR genes show a substitution rate much lower than the synonymous rate. Moreover, paired and unpaired nucleotide sites of miR genes tend to remain unchanged during evolution. Therefore, once miR genes acquired their functions, they appear to have evolved very slowly, maintaining essentially the same structures for a long time.

关键词： birth-and-death evolution gene duplication gene regulation multigene family noncoding rna substitution rate

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A Simplified System to Express Circularized Inhibitors of mirna for Stable and Potent Suppression of mirna Functions

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MOLECULAR THERAPY-NUCLEIC ACIDS 2018年 13卷 556-567页

作者： Shu, Yi Wu, Ke Zeng, Zongyue Huang, Shifeng Ji, Xiaojuan Yuan, Chengfu Zhang, Linghuan Liu, Wei Huang, Bo Feng, Yixiao Zhang, Bo Dai, Zhengyu Shen, Yi Luo, Wenping Wang, Xi Liu, Bo Lei, Yan Ye, Zhenyu Zhao, Ling Cao, Daigui Yang, Lijuan Chen, Xian Luu, Hue H. Reid, Russell R. Wolf, Jennifer Moriatis Lee, Michael J. He, Tong-Chuan Chongqing Med Univ Stem Cell Biol & Therapy Lab Minist Educ Key Lab Child Dev & DisordersChildrens Hosp Chongqing 400014 Peoples R China Univ Chicago Med Ctr Mol Oncol Lab Dept Orthopaed Surg & Rehabil Med 5841 South Maryland AveMC 3079 Chicago IL 60637 USA Chongqing Med Univ Minist Educ Key Lab Diagnost Med Sch Lab MedAffiliated Hosp Chongqing 400016 Peoples R China Chongqing Med Univ Sch Pharm Dept Pharmacol Chongqing 400046 Peoples R China China Three Gorges Univ Dept Biochem & Mol Biol Sch Med Yichang 443002 Peoples R China Nanchang Univ Dept Clin Lab Med Affiliated Hosp 2 Nanchang 330006 Jiangxi Peoples R China Lanzhou Univ Key Lab Orthopaed Surg Gansu Prov Hosp 1 Lanzhou 730030 Gansu Peoples R China Lanzhou Univ Key Lab Orthopaed Surg Gansu Prov Hosp 2 Lanzhou 730030 Gansu Peoples R China Lanzhou Univ Dept Orthopaed Surg Hosp 1 Lanzhou 730030 Gansu Peoples R China Lanzhou Univ Dept Obstet & Gynecol Hosp 1 Lanzhou 730030 Gansu Peoples R China Lanzhou Univ Dept Orthopaed Surg Hosp 2 Lanzhou 730030 Gansu Peoples R China Lanzhou Univ Dept Obstet & Gynecol Hosp 2 Lanzhou 730030 Gansu Peoples R China Chongqing Hosp Tradit Chinese Med Dept Orthopaed Surg Chongqing 400021 Peoples R China Cent S Univ Dept Orthopaed Surg Xiangya Hosp 2 Changsha 410011 Hunan Peoples R China Soochow Univ Dept Gen Surg Affiliated Hosp 2 Suzhou 215004 Peoples R China Qingdao Univ Dept Clin Lab Med Affiliated Hosp Qingdao 266061 Peoples R China Univ Chicago Med Ctr Dept Surg Sect Plast Surg Chicago IL 60637 USA

Micrornas (mirnas) are an evolutionarily conserved class of small regulatory noncoding rnas, binding to complementary target mrnas and resulting in mrna translational inhibition or degradation, and they play an important role in regulating many aspects of physiologic and pathologic processes in mammalian cells. Thus, efficient manipulations of mirna functions may be exploited as promising therapeutics for human diseases. Two commonly used strategies to inhibit mirna functions include direct transfection of chemically synthesized mirna inhibitors and delivery of a gene vector that instructs intracellular transcription of mirna inhibitors. While most mirna inhibitors are based on antisense molecules to bind and sequester mirnas from their natural targets, it is challenging to achieve effective and stable mirna inhibition. Here we develop a user-friendly system to express circular inhibitors of mirna (CimiRs) by exploiting the noncanonical head-to-tail backsplicing mechanism for generating endogenous circular rna sponges. In our proof-of-principle experiments, we demonstrate that the circular forms of the hsa-miR223-binding site of human beta-arrestin1 (ARRB1) 3' UTR sponge rna (BUTR), the bulged anti-miR223 (cirBulg223) and bulged anti-miR21 (cirBulg21), exhibit more potent suppression of mirna functions than their linear counterparts. Therefore, the engineered CimiR expression system should be a valuable tool to target mirnas for basic and translational research.

关键词： microrna mirna mirna sponge circular rna mirna inhibitor competing endogenous rna mirna decoy noncoding rna oncomiR

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MIWI-independent small rnas (MSY-rnas) bind to the rna-binding protein, MSY2, in male germ cells

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2009年第30期106卷 12371-12376页

作者： Xu, Mingang Medvedev, Sergey Yang, Juxiang Hecht, Norman B. Univ Penn Sch Med Ctr Res Reprod & Womens Hlth Dept Obstet & Gynecol Philadelphia PA 19104 USA Univ Penn Dept Biol Philadelphia PA 19104 USA

The germ cell-specific DNA/rna-binding protein MSY2 binds small rnas (MSY-rnas) that are approximate to 25-31 nt in length, often initiate with a 5' adenine, and are expressed in both germ cells and somatic cells. MSY-rna levels do not decrease in Miwi or Msy2 null mice. Most MSY-rnas map within annotated genes, but some are PIWI-interacting rna (pirna)-like and map to pirna clusters. MSY-rnas are in both nuclei and cytoplasm. In nuclei, MSY-rnas are enriched in chromatin, and in the cytoplasm they are detected in both ribonucleoproteins and polysomes.

关键词： noncoding rna rna-protein interactions Y box proteins spermatogenesis

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Functions of Monocytes and Macrophages and the Associated Effective Molecules and Mechanisms at the Early Stage of Atherosclerosis

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ACTA CARDIOLOGICA SINICA 2021年第5期37卷 522-533页

作者： Jin, Liyuan Deng, Zihui Bai, Yongyi Ye, Ping Chinese Peoples Liberat Army Gen Hosp Med Ctr 1 Natl Clin Res Ctr Geriatr Dis Dept Cardiol 28 Fuxing Rd Beijing 100853 Peoples R China Gen Hosp Chinese Peoples Liberat Army Biochem Dept Grad Sch Beijing Peoples R China

Objective: This study aimed to explore the functions and possible underlying regulatory molecules and mechanisms of monocytes and macrophages under early atherosclerotic conditions. Methods: THP-1-derived monocytes or macrophages were induced by 50 g/ml oxidized low density lipoprotein (ox-LDL) for 24 hours, and the degree of lipid metabolism and inflammation were determined. In addition, we identified differentially expressed genes, noncoding ribonucleic acids (rnas), pathways and mechanisms by rna sequencing, and performed further correlation analysis and molecular expression verification. Results: Monocytes could not form foam cells with oil red 0 staining directly and had low levels of lipids as determined by total cholesterol and triglycerides assays, cholesterol uptake molecules CD36, the class A macrophage scavenger receptor and lectin-like oxidized low-density lipoprotein receptor-1 and cholesterol efflux molecules ATP binding cassette transporter Al, ATP binding cassette transporter G1 and liver X receptor a, and inflammatory factors, which were markedly different from those in macrophages. Additionally, sequencing data showed obviously differentially expressed genes, micrornas and long noncoding rnas in the atherosclerotic group. We identified 15 upregulated and downregulated genes, and 10 biological processes and pathways involved in atherosclerosis. Specifically, fatty acid desaturase 2 and apolipoprotein Al in the peroxisome proliferator-activated receptor signaling pathway were differentially expressed in stimulated macrophages, whereas no changes were observed in the monocyte groups. Furthermore, correlation analysis showed differential expressed Incrnas targeting mirnas and mrnas, and 24 competing endogenous rna (cerna) networks of long noncoding rna-microrna-messenger rna in early oxidative macrophages. Conclusions: Monocytes did not directly participate in lipid metabolism before differentiation into macrophages at the early stage in vitro. Further

关键词： Atherosclerosis Competing endogenous rna Lipid metabolism Macrophage Monocyte noncoding rna

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Monophyletic Origin and Divergent Evolution of Animal Telomerase rna

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MOLECULAR BIOLOGY AND EVOLUTION 2021年第1期38卷 215-228页

作者： Logeswaran, Dhenugen Li, Yang Podlevsky, Joshua D. Chen, Julian J-L Arizona State Univ Sch Mol Sci Tempe AZ 85281 USA Sandia Natl Labs Mol & Microbiol Dept Albuquerque NM 87185 USA

Telomerase rna (TR) is a noncoding rna essential for the function of telomerase ribonucleoprotein. TRs from vertebrates, fungi, ciliates, and plants exhibit extreme diversity in size, sequence, secondary structure, and biogenesis pathway. However, the evolutionary pathways leading to such unusual diversity among eukaryotic kingdoms remain elusive. Within the metazoan kingdom, the study of TR has been limited to vertebrates and echinoderms. To understand the origin and evolution of TR across the animal kingdom, we employed a phylogeny-guided, structure-based bioinformatics approach to identify 82 novel TRs from eight previously unexplored metazoan phyla, including the basal-branching sponges. Synthetic TRs from two representative species, a hemichordate and a mollusk, reconstitute active telomerase in vitro with their corresponding telomerase reverse transcriptase components, confirming that they are authentic TRs. Comparative analysis shows that three functional domains, template-pseudoknot (T-PK), CR4/5, and box H/ACA, are conserved between vertebrate and the basal metazoan lineages, indicating a monophyletic origin of the animal TRs with a snorna-related biogenesis mechanism. Nonetheless, TRs along separate animal lineages evolved with divergent structural elements in the T-PK and CR4/5 domains. For example, TRs from echinoderms and protostomes lack the canonical CR4/5 and have independently evolved functionally equivalent domains with different secondary structures. In the T-PK domain, a P1.1 stem common in most metazoan clades defines the template boundary, which is replaced by a P1-defined boundary in vertebrates. This study provides unprecedented insight into the divergent evolution of detailed TR secondary structures across broad metazoan lineages, revealing ancestral and later-diversified elements.

关键词： noncoding rna homology search rna structure telomere ribonucleoprotein

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A novel assessing system for predicting the prognosis of gastric cancer

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EPIGENOMICS 2019年第11期11卷 1251-1266页

作者： Lin, Siheng Zhou, Rui Zeng, Dongqiang Wu, Jiani Wu, Jianhua Zhang, Jingwen Sun, Huiying Zhu, Shaowei Shi, Min Bin, Jianping Liao, Yulin Liao, Wangjun Southern Med Univ Nanfang Hosp Dept Oncol Guangzhou Guangdong Peoples R China Southern Med Univ Nanfang Hosp Dept Med Ultrason Guangzhou Guangdong Peoples R China Southern Med Univ Nanfang Hosp Dept Cardiol State Key Lab Organ Failure Res Guangzhou Guangdong Peoples R China

Aim: To develop novel diagnostic tools that can predict the prognosis of gastric cancer. Material & methods: Using rna expression data from The Cancer Genome Atlas and Gene Expression Omnibus, we established protein-coding rnas-noncoding rnas-tumor microenvironment type (PNM) scores, which contain signatures of tumor protein coding genes (P), tumor noncoding genes (N) and immune/stroma cells in tumor microenvironment (M) to predict the prognosis of gastric cancer. Results & conclusion: Based on PNM scores, gastric cancer patients were divided into three subgroups and Kaplan-Meier survival curves revealed significant differences among the subgroups (p < 0.001). Our study showed that the PNM scores could be used as a robust predicting tool for the prognosis of gastric cancer.

关键词： gastric cancer immunotherapy noncoding rna prognosis tumor microenvironment

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micrornas in the pathophysiology of epilepsy

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NEUROSCIENCE LETTERS 2018年第0期667卷 47-52页

作者： Brennan, Gary P. Henshall, David C. Royal Coll Surgeons Ireland Dept Physiol & Med Phys 123 St Stephens Green Dublin D02 YN77 Ireland

Temporal lobe epilepsy is a common and often drug-resistant seizure disorder. The underlying pathological processes which give rise to the development of spontaneous seizures include neuroinflammation, cell loss, neurogenesis and dendritic abnormalities and many of these are driven by insult-induced changes in gene expression and gene expression regulation. Micrornas are powerful modulators of post-transcriptional gene expression which are dysregulated during epileptogenesis. The advent of locked nucleic acid (LNA) based inhibitory methods and mimic technology has facilitated in vivo functional assessment of these molecules in epilepsy. Here we review recent advances in our understanding of the role of these short non-coding rnas in the pathophysiology of epilepsy. (C) 2017 Elsevier B.V. All rights reserved.

关键词： Epigenetics Hippocampal sclerosis noncoding rna Oligonucleotide

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Detailed mapping of the ERG-ETS2 interval of human chromosome 21 and comparison with the region of conserved synteny on mouse chromosome 16

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GENE 2004年第324期324卷 65-77页

作者： Owczarek, CM Portbury, KJ Hardy, MP O'Leary, DA Kudoh, J Shibuya, K Shimizu, N Kola, I Hertzog, PJ Monash Univ Monash Inst Reprod & Dev Ctr Funct Genom & Human Dis Clayton Vic 3168 Australia Keio Univ Sch Med Dept Mol Biol Tokyo 1608582 Japan

We have carried out a detailed annotation of 550 kb of genomic DNA on human chromosome 21 containing the ERG and ETS2 genes. Comparative genomic analysis between this region and the interval of conserved synteny on mouse chromosome 16 indicated that the order and orientation of the ERG and ETS2 genes were conserved and revealed several regions containing potential conserved noncoding sequences. Four pseudogenes including those for small protein G, laminin receptor, human transposase protein and meningioma-expressed antigen were identified. A potentially novel gene (C21orf24) with alternative mrna transcripts, consensus splice donor and acceptor sites, but no coding potential nor murine orthologue, was identified and found to be expressed in a range of human cell lines. We have identified four novel splice variants, that arise from a previously undescribed 5' exon of the human ERG gene. Comparison of the cDNA sequences enabled us to determine the complete exon-intron structure of the ERG gene. We have also identified the presence of noncoding rnas in the first and second introns of the ETS2 gene. Our studies have important implications for Down syndrome as this region contains multiple mrna transcripts, both coding and potentially noncoding, that may play as yet undescribed roles in the pathogenesis of this disorder. (C) 2003 Elsevier B.V. All rights reserved.

关键词： Down syndrome genomic structure noncoding rna pseudogene alternative transcript

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noncoding transcription within the Igh distal V_H region at PAIR elements affects the 3D structure of the Igh locus in pro-B cells

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2012年第42期109卷 17004-17009页

作者： Verma-Gaur, Jiyoti Torkamani, Ali Schaffer, Lana Head, Steven R. Schork, Nicholas J. Feeney, Ann J. Scripps Res Inst Dept Immunol & Microbial Sci La Jolla CA 92037 USA Scripps Translat Sci Inst La Jolla CA 92037 USA Scripps Res Inst Dept Mol & Expt Med La Jolla CA 92037 USA Scripps Res Inst Next Generat Sequencing Core Facil La Jolla CA 92037 USA

noncoding sense and antisense germ-line transcription within the Ig heavy chain locus precedes V(D)J recombination and has been proposed to be associated with Igh locus accessibility, although its precise role remains elusive. However, no global analysis of germline transcription throughout the Igh locus has been done. Therefore, we performed directional rna-seq, demonstrating the locations and extent of both sense and antisense transcription throughout the Igh locus. Surprisingly, the majority of antisense transcripts are localized around two Pax5-activated intergenic repeat (PAIR) elements in the distal IghV region. Importantly, long-distance loops measured by chromosome conformation capture (3C) are observed between these two active PAIR promoters and E mu, the start site of E mu germ-line transcription, in a lineage-and stage-specific manner, even though this antisense transcription is E mu-independent. YY1(-/-) pro- B cells are greatly impaired in distal V-H gene rearrangement and Igh locus compaction, and we demonstrate that YY1 deficiency greatly reduces antisense transcription and PAIR-E mu interactions. ChIP-seq shows high level YY1 binding only at E mu, but low levels near some antisense promoters. PAIR-E mu interactions are not disrupted by DRB, which blocks transcription elongation without disrupting transcription factories once they are established, but the looping is reduced after heat-shock treatment, which disrupts transcription factories. We propose that transcription-mediated interactions, most likely at transcription factories, initially compact the Igh locus, bringing distal VH genes close to the DJ(H) rearrangement which is adjacent to E mu. Therefore, we hypothesize that one key role of noncoding germ-line transcription is to facilitate locus compaction, allowing distal V-H genes to undergo efficient rearrangement.

关键词： noncoding rna V(D)J rearrangement CTCF long-range interactions

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Biological Activities of Extracellular Vesicles and Their Cargos from Bovine and Human Milk in Humans and Implications for Infants

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JOUrnaL OF NUTRITION 2017年第1期147卷 3-10页

作者： Zempleni, Janos Aguilar-Lozano, Ana Sadri, Mahrou Sukreet, Sonal Manca, Sonia Wu, Di Zhou, Fang Mutai, Ezra Univ Nebraska Lincoln Dept Nutr & Hlth Sci Lincoln NE 68588 USA

Extracellular vesicles (EVs) in milk harbor a variety of compounds, including lipids, proteins, noncoding rnas, and mrnas. Among the various classes of EVs, exosomes are of particular interest, because cargo sorting in exosomes is a regulated, nonrandom process and exosomes play essential roles in cell-to-cell communication. Encapsulation in exosomes confers protection against enzymatic and nonenzymatic degradation of cargos and provides a pathway for cellular uptake of cargos by endocytosis of exosomes. Compelling evidence suggests that exosomes in bovine milk are transported by intestinal cells, vascular endothelial cells, and macrophages in human and rodent cell cultures, and bovine-milk exosomes are delivered to peripheral tissues in mice. Evidence also suggests that cargos in bovine-milk exosomes, in particular rnas, are delivered to circulating immune cells in humans. Some micrornas and mrnas in bovine-milk exosomes may regulate the expression of human genes and be translated into protein, respectively. Some exosome cargos are quantitatively minor in the diet compared with endogenous synthesis. However, noncanonical pathways have been identified through which low concentrations of dietary micrornas may alter gene expression, such as the accumulation of exosomes in the immune cell microenvironment and the binding of micrornas to Toll-like receptors. Phenotypes observed in infant feeding studies include higher Mental Developmental Index, Psychomotor Development Index, and Preschool Language Scale-3 scores in breastfed infants than in those fed various formulas. In mice, supplementation with plant-derived MIR-2911 improved the antiviral response compared with controls. Porcine-milk exosomes promote the proliferation of intestinal cells in mice. This article discusses the above-mentioned advances in research concerning milk exosomes and their cargos in human nutrition. Implications for infant nutrition are emphasized, where permitted, but data in infants are limit

关键词： biological activity bovine milk human milk microrna noncoding rna exosomes extracellular vesicles infants

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