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rna sequencing revealing the role of AMP-activated protein kinase signaling in mice myocardial ischemia reperfusion injury

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GENE 2019年 703卷 91-101页

作者： Sun, Huankun Wang, Jiaoni Que, Jiaqun Peng, Yangpei Yu, Yongwei Wang, Lei Ye, Haihao Huang, Kaiyu Xue, Yangjing Zhou, Yingying Ji, Kangting Second Affiliated Hosp Dept Cardiol Wenzhou 325000 Zhejiang Peoples R China Wenzhou Med Univ Yuying Childrens Hosp Wenzhou 325000 Zhejiang Peoples R China Zhejiang Univ Dept Diagnost Ultrasound & Echocardiog Sir Run Run Shaw Hosp Sch Med Hangzhou 310016 Zhejiang Peoples R China Wenzhou Hosp Tradit Chinese Med Dept Cardiol Wenzhou 325000 Zhejiang Peoples R China Second Affiliated Hosp Dept Endocrinol Wenzhou 325000 Zhejiang Peoples R China

Long non-coding rnas (lncrna) and circular rnas (circrna) that sponge mirnas could indirectly regulate gene expression, contributing to certain biological processes. This study aimed to investigate the role of non coding rnas in the pathogenesis of myocardial ischemia reperfusion-injury (MIRI). MIRI in male C578/6J mice was induced by left anterior descending coronary artery ligation occlusion for 30 min, and 4 h of reperfusion. rna sequencing was performed to obtain the mrna and non-coding rna expression profiles of the MIRI and sham groups. Bioinformatic methods were used to analyze the co-expression rnas, mirna binding sites and competitive endogenous rna (cerna) pairs. Differentially expressed rnas were identified with a cutoff fold change > 2 and p < 0.05. A total of 64 mrnas were upregulated and 98 mrnas were downregulated, and 10 lncrnas were upregulated and 10 lncrnas were downregulated. All altered (p < 0.05) mrnas were selected for gene ontology and pathway analysis. The AMP-activated protein kinase (AMPK) signaling pathway was enriched in the downregulated genes, and the activation of AMPK was confirmed by western blotting. The lncrna co-expression network and cerna network base on genes in AMPK signaling pathway were then constructed, revealing that ENSMUST00000147762.7 and TUCP_000184 might be key regulators in MIRI induced AMPK activation. The expression levels of AMPK signaling-related rnas and those involved in the cerna network were validated using qRT-PCR. Overall, this study identified potential new targets on AMPK signaling in MIRI.

关键词： Myocardial ischemia reperfusion injury Competitive endogenous rna rna profiling non-coding rna Cellular signaling

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An rna Degradation Machine Sculpted by Ro Autoantigen and noncoding rna

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CELL 2013年第1期153卷 166-177页

作者： Chen, Xinguo Taylor, David W. Fowler, Casey C. Galan, Jorge E. Wang, Hong-Wei Wolin, Sandra L. Yale Univ Sch Med Dept Cell Biol New Haven CT 06510 USA Yale Univ Sch Med Dept Mol Biophys & Biochem New Haven CT 06510 USA Yale Univ Sch Med Dept Microbial Pathogenesis New Haven CT 06510 USA

Many bacteria contain an ortholog of the Ro autoantigen, a ring-shaped protein that binds noncoding rnas (ncrnas) called Y rnas. In the only studied bacterium, Deinococcus radiodurans, the Ro ortholog Rsr functions in heat-stress-induced ribosomal rna (rrna) maturation and starvation-induced rrna decay. However, the mechanism by which this conserved protein and its associated ncrnas act has been obscure. We report that Rsr and the exoribonuclease polynucleotide phosphorylase (PNPase) form an rna degradation machine that is scaffolded by Y rna. Single-particle electron microscopy, followed by docking of atomic models into the reconstruction, suggests that Rsr channels single-stranded rna into the PNPase cavity. Biochemical assays reveal that Rsr and Y rna adapt PNPase for effective degradation of structured rnas. A Ro ortholog and ncrna also associate with PNPase in Salmonella Typhimurium. Our studies identify another ribonucleoprotein machine and demonstrate that ncrna, by tethering a protein cofactor, can alter the substrate specificity of an enzyme.

关键词： non-coding rna AUTOANTIGENS HEAT -- Physiological effect DEINOCOCCUS radiodurans EXORIBONUCLEASES POLYNUCLEOTIDE phosphorylase

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X chromosome inactivation: silencing, topology and reactivation

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CURRENT OPINION IN CELL BIOLOGY 2017年第0期46卷 54-61页

作者： Finestra, Teresa Robert Gribnau, Joost Erasmus MC Dept Dev Biol Wytemaweg 80 NL-3015 CN Rotterdam Netherlands

To ensure X-linked gene dosage compensation between females (XX) and males (XY), one X chromosome undergoes X chromosome inactivation (XCI) in female cells. This process is tightly regulated throughout development by many different factors, with Xist as a key regulator, encoding a long non-coding rna, involved in establishment of several layers of repressive epigenetic modifications. Several recent studies on XCI focusing on identification and characterization of Xist rna-protein interactors, revealed new factors involved in gene silencing, genome topology and nuclear membrane attachment, amongst others. Also, new insights in higher order chromatin organization have been presented, revealing differences between the topological organization of active and inactive X chromosomes (Xa and Xi), with associated differences in gene expression. Finally, further evidence indicates that the inactive state of the Xi can be (partially) reversed, and that this X chromosome reactivation (XCR) might be associated with disease.

关键词： CHROMOSOMES DOSAGE forms of drugs non-coding rna EPIGENETICS GENE expression

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The Rejuvenation and Functional Restoration of Aged Adipose Stem Cells by DUXAP10 Knockdown via the Regulation of the miR-214-3p/RASSF5 Axis

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STEM CELLS TRANSLATIONAL MEDICINE 2024年第5期13卷 462-476页

作者： Ren, Sen Li, Chengcheng Xiong, Hewei Wu, Qian Wu, Xiaohui Xiong, Zhongwei Dong, Lixing Shu, Bing Wei, Wei Ma, Chao Li, Xiang Chen, Jincao Wuhan Univ Zhongnan Hosp Dept Neurosurg Wuhan 430071 Peoples R China Huazhong Univ Sci & Technol Union Hosp Tongji Med Coll Dept Hand Surg Wuhan Peoples R China Huazhong Univ Sci & Technol Tongji Med Coll Union Hosp Dept Emergency Surg Wuhan Peoples R China Wuhan Univ Brain Res Ctr Zhongnan Hosp Wuhan Peoples R China Wuhan Univ Med Res Inst Wuhan Peoples R China

Adipose stem cell (ASC)-based therapies provide an encouraging option for tissue repair and regeneration. However, the function of these cells declines with aging, which limits their clinical transformation. Recent studies have outlined the involvement of long non-coding rnas in stem cell aging. Here, we reanalyzed our published rna sequencing (rna-seq) data profiling differences between ASCs from young and old donors and identified a lncrna named double homeobox A pseudogene 10 (DUXAP10) as significantly accumulated in aged ASCs. Knocking down DUXAP10 promoted stem cell proliferation and migration and halted cell senescence and the secretion of proinflammatory cytokines. In addition, DUXAP10 was located in the cytoplasm and functioned as a decoy for miR-214-3p. miR-214-3p was downregulated in aged ASCs, and its overexpression rejuvenated aged ASCs and reversed the harm caused by DUXAP10. Furthermore, Ras Association Domain Family Member 5 (RASSF5) was the target of miR-214-3p and was upregulated in aged ASCs. Overexpressing DUXAP10 and inhibiting miR-214-3p both enhanced RASSF5 content in ASCs, while DUXAP10 knockdown promoted the therapeutic ability of aged ASCs for skin wound healing. Overall, this study offers new insights into the mechanism of age-related ASC dysfunction and names DUXAP10 and miR-214-3p as potential targets for energizing aged stem cells. Graphical Abstract

关键词： adipose stem cell aging non-coding rna DUXAP10 miR-214-3p RASSF5

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rna Polymerase II Collision Interrupts Convergent Transcription

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MOLECULAR CELL 2012年第3期48卷 365-374页

作者： Hobson, David J. Wei, Wu Steinmetz, Lars M. Svejstrup, Jesper Q. Canc Res UK London Res Inst Clare Hall Labs Mech Transcript Lab London EN6 3LD England European Mol Biol Lab Genome Biol Unit D-69117 Heidelberg Germany Stanford Genome Technol Ctr Palo Alto CA 94304 USA

Antisense noncoding transcripts, genes-within-genes, and convergent gene pairs are prevalent among eukaryotes. The existence of such transcription units raises the question of what happens when rna polymerase II (rnaPII) molecules collide head-to-head. Here we use a combination of biochemical and genetic approaches in yeast to show that polymerases transcribing opposite DNA strands cannot bypass each other. rnaPII stops but does not dissociate upon head-to-head collision in vitro, suggesting that opposing polymerases represent insurmountable obstacles for each other. Head-to-head collision in vivo also results in rnaPII stopping, and removal of collided rnaPII from the DNA template can be achieved via ubiquitylation-directed proteolysis. Indeed, in cells lacking efficient rnaPII polyubiquitylation, the half-life of collided polymerases increases, so that they can be detected between convergent genes. These results provide insight into fundamental mechanisms of gene traffic control and point to an unexplored effect of antisense transcription on gene regulation via polymerase collision.

关键词： rna polymerases TRANSCRIPTION factors ANTISENSE rna non-coding rna GENETIC transcription EUKARYOTES MOLECULE-molecule collisions

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The green tea polyphenol EGCG inhibits E-coli biofilm formation by impairing amyloid curli fibre assembly and downregulating the biofilm regulator CsgD via the σ^E-dependent srna RybB

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MOLECULAR MICROBIOLOGY 2016年第1期101卷 136-151页

作者： Serra, Diego O. Mika, Franziska Richter, Anja M. Hengge, Regine Humboldt Univ Inst Biol Mikrobiol D-10115 Berlin Germany

In bacterial biofilms, which are often involved in chronic infections, cells are surrounded by a self-produced extracellular matrix that contains amyloid fibres, exopolysaccharides and other biopolymers. The matrix contributes to the pronounced resistance of biofilms against antibiotics and host immune systems. Being highly inflammatory, matrix amyloids such as curli fibres of Escherichia coli can also play a role in pathogenicity. Using macrocolony biofilms of commensal and pathogenic E. coli as a model system, we demonstrate here that the green tea polyphenol epigallocatachin gallate (EGCG) is a potent antibiofilm agent. EGCG virtually eliminates the biofilm matrix by directly interfering with the assembly of curli subunits into amyloid fibres, and by triggering the sigma(E) cell envelope stress response and thereby reducing the expression of CsgD - a crucial activator of curli and cellulose biosynthesis - due to csgD mrna targeting by the sigma(E)-dependent srna RybB. These findings highlight EGCG as a potential adjuvant for antibiotic therapy of biofilm-associated infections. Moreover, EGCG may support therapies against pathogenic E. coli that produce inflammatory curli fibres along with Shigatoxin.

关键词： POLYPHENOLS non-coding rna BIOFILMS MICROBIAL exopolysaccharides DOWN-regulation (Biology) BIOPOLYMERS

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Identifying multi-layer gene regulatory modules from multi-dimensional genomic data

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BIOINFORMATICS 2012年第19期28卷 2458-2466页

作者： Li, Wenyuan Zhang, Shihua Liu, Chun-Chi Zhou, Xianghong Jasmine Univ So Calif Dept Biol Sci Program Mol & Computat Biol Los Angeles CA 90089 USA Chinese Acad Sci Acad Math & Syst Sci Natl Ctr Math & Interdisciplinary Sci Beijing 100190 Peoples R China Natl Chung Hsing Univ Inst Genom & Bioinformat Taichung 402 Taiwan

Motivation: Eukaryotic gene expression (GE) is subjected to precisely coordinated multi-layer controls, across the levels of epigenetic, transcriptional and post-transcriptional regulations. Recently, the emerging multi-dimensional genomic dataset has provided unprecedented opportunities to study the cross-layer regulatory interplay. In these datasets, the same set of samples is profiled on several layers of genomic activities, e. g. copy number variation (CNV), DNA methylation (DM), GE and microrna expression (ME). However, suitable analysis methods for such data are currently sparse. Results: In this article, we introduced a sparse Multi-Block Partial Least Squares (sMBPLS) regression method to identify multi-dimensional regulatory modules from this new type of data. A multi-dimensional regulatory module contains sets of regulatory factors from different layers that are likely to jointly contribute to a local 'gene expression factory'. We demonstrated the performance of our method on the simulated data as well as on The Cancer Genomic Atlas Ovarian Cancer datasets including the CNV, DM, ME and GE data measured on 230 samples. We showed that majority of identified modules have significant functional and transcriptional enrichment, higher than that observed in modules identified using only a single type of genomic data. Our network analysis of the modules revealed that the CNV, DM and microrna can have coupled impact on expression of important oncogenes and tumor suppressor genes.

关键词： GENE regulatory networks GENOMICS GENE expression EUKARYOTIC genomes non-coding rna DNA methylation EPIGENETICS

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Increased expression of H19 non-coding mrna follows hepatocyte proliferation in the rat and mouse

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JOUrnaL OF HEPATOLOGY 2004年第5期40卷 808-814页

作者： Yamamoto, Y Nishikawa, Y Tokairin, T Omori, Y Enomoto, K Akita Univ Sch Med Dept Pathol Akita 0108543 Japan

Background/Aims: H19 is a paternally imprinted gene that is believed to function as non-coding mrna. While H19 is only faintly expressed in the normal adult liver, it is abundantly expressed during the fetal period. We explored the possibility that H19 might participate in the regulation of hepatocyte proliferation. Methods: Adult male rats and mice were subjected to a two-thirds partial hepatectomy, and after various time periods, hepatocytes were isolated and analyzed for H19 gene expression. The expression was also examined in cultured rat hepatocytes. Results: The expression of H19 was dramatically increased after 2 days (rat) and 4 days (mouse), peaked at 3 days (rat) and 6 days (mouse), and then gradually declined. In both species, the increase in U19 gene expression was preceded by the induction of proliferating cell nuclear antigen and DNA synthesis. An allele-specific RT-PCR analysis in the mouse showed that the paternally imprinted status of the gene was maintained after a partial hepatectomy. H19 was strongly induced in spheroid cultures after transient hepatocyte proliferation, but not in conventional monolayer cultures, in which persistent proliferation occurred. Conclusions: Our results demonstrated that H19 gene expression was dynamically regulated in adult hepatocytes in close association with their proliferation. (C) 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

关键词： H19 non-coding rna genomic imprinting liver regeneration hepatocytes

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Overlapping transcripts, double-stranded rna and antisense regulation: A genomic perspective

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CELLULAR AND MOLECULAR LIFE SCIENCES 2006年第18期63卷 2102-2118页

作者： Munroe, S. H. Zhu, J. Duke Univ Inst Genome Sci & Policy Durham NC 27708 USA Marquette Univ Dept Biol Sci Milwaukee WI 53233 USA

Bioinformatic analysis of the transcriptomes of diverse eukaryotes has demonstrated the ubiquity and structural diversity of complementary antisense rnas. These include both trans-encoded micrornas and a large population of cis-encoded antisense rnas that encompasses both coding and non-coding rnas. Antisense regulation has previously been characterized primarily as a post-transcriptional response affecting rna stability, nuclear processing, export, or translation. However, the formation of double-stranded (ds) rnas by base-pairing between complementary rnas may elicit regulatory responses at the transcriptional level as well. Analysis of antisense transcription at several imprinted loci has suggested a number of other mechanisms that may not require formation of dsrna. Understanding the integration of transcriptional and post-transcriptional regulatory mechanisms represents a major challenge for understanding antisense regulation in eukaryotes. Such insight is also essential for understanding general principles of genetic regulation within the complex genomes characteristic of mouse and man as well as those of other eukaryotes.

关键词： antisense rna microrna non-coding rna rna interference rna-rna base pairing double-stranded rna

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Plasticity of archaeal C/D box srna biogenesis

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MOLECULAR MICROBIOLOGY 2017年第1期103卷 151-164页

作者： Tripp, Vanessa Martin, Roman Orell, Alvaro Alkhnbashi, Omer S. Backofen, Rolf Randau, Lennart Max Planck Inst Terr Microbiol Karl von Frisch Str 10 D-35043 Marburg Germany SYNMIKRO LOEWE Ctr Synthet Microbiol Karl von Frisch Str 16 D-35043 Marburg Germany Univ Freiburg Dept Comp Sci Bioinformat Grp Georges Kohler Allee 106 D-79110 Freiburg Germany Univ Freiburg Cluster Excellence BIOSS Ctr Biol Signalling Studies Freiburg Germany

Archaeal and eukaryotic organisms contain sets of C/D box s(no) rnas with guide sequences that determine ribose 2'-O-methylation sites of target rnas. The composition of these C/D box srna sets is highly variable between organisms and results in varying rna modification patterns which are important for ribosomal rna folding and stability. Little is known about the genomic organization of C/D box srna genes in archaea. Here, we aimed to obtain first insights into the biogenesis of these archaeal C/D box srnas and analyzed the genetic context of more than 300 archaeal srna genes. We found that the majority of these genes do not possess independent promoters but are rather located at positions that allow for co-transcription with neighboring genes and their start or stop codons were frequently incorporated into the conserved boxC and D motifs. The biogenesis of plasmid-encoded C/D box srna variants was analyzed in vivo in Sulfolobus acidocaldarius. It was found that C/D box srna maturation occurs independent of their genetic context and relies solely on the presence of intact rna kink-turn structures. The observed plasticity of C/D box srna biogenesis is suggested to enable their accelerated evolution and, consequently, allow for adjustments of the rna modification landscape.

关键词： non-coding rna ORIGIN of life RIBOSE EUKARYOTES PSEUDOURIDINE

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