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Emerging connections between rna and autophagy

AUTOPHAGY 2017年第1期13卷 3-23页

作者： Frankel, Lisa B. Lubas, Michal Lund, Anders H. Univ Copenhagen Biotech Res & Innovat Ctr Ole Maaloes Vej 5 DK-2200 Copenhagen Denmark

Macroautophagy/autophagy is a key catabolic process, essential for maintaining cellular homeostasis and survival through the removal and recycling of unwanted cellular material. Emerging evidence has revealed intricate connections between the rna and autophagy research fields. While a majority of studies have focused on protein, lipid and carbohydrate catabolism via autophagy, accumulating data supports the view that several types of rna and associated ribonucleoprotein complexes are specifically recruited to phagophores (precursors to autophagosomes) and subsequently degraded in the lysosome/vacuole. Moreover, recent studies have revealed a substantial number of novel autophagy regulators with rna-related functions, indicating roles for rna and associated proteins not only as cargo, but also as regulators of this process. In this review, we discuss widespread evidence of rna catabolism via autophagy in yeast, plants and animals, reviewing the molecular mechanisms and biological importance in normal physiology, stress and disease. In addition, we explore emerging evidence of core autophagy regulation mediated by rna-binding proteins and noncoding rnas, and point to gaps in our current knowledge of the connection between rna and autophagy. Finally, we discuss the pathological implications of rna-protein aggregation, primarily in the context of neurodegenerative disease.

关键词： autophagy granulophagy noncoding rna ribophagy rna-binding proteins rna degradation

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DNA-Damage Response rna-Binding Proteins (DDRBPs): Perspectives from a New Class of Proteins and Their rna Targets

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JOUrnaL OF MOLECULAR BIOLOGY 2017年第21期429卷 3139-3145页

作者： Dutertre, Martin Vagner, Stephan PSL Res Univ Inst Curie CNRS UMR3348 F-91405 Orsay France Univ Paris Saclay Univ Paris Sud CNRS UMR3348 F-91405 Orsay France Equipe Labellisee Ligue Canc Orsay France

Upon DNA damage, cells trigger an early DNA-damage response (DDR) involving DNA repair and cell cycle checkpoints, and late responses involving gene expression regulation that determine cell fate. Screens for genes involved in the DDR have found many rna-binding proteins (RBPs), while screens for novel RBPs have identified DDR proteins. An increasing number of RBPs are involved in early and/or late DDR. We propose to call this new class of actors of the DDR, which contain an rna-binding activity, DNA-damage response rna-binding proteins (DDRBPs). We then discuss how DDRBPs contribute not only to gene expression regulation in the late DDR but also to early DDR signaling, DNA repair, and chromatin modifications at DNA-damage sites through interactions with both long and short noncoding rnas. (C) 2016 Elsevier Ltd. All rights reserved.

关键词： genotoxic stress DNA repair noncoding rna post-transcriptional regulation chromatin modification

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Both maternally and paternally imprinted genes regulate seed development in rice

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NEW PHYTOLOGIST 2017年第2期216卷 373-387页

作者： Yuan, Jingya Chen, Sushu Jiao, Wu Wang, Longfei Wang, Limei Ye, Wenxue Lu, Jie Hong, Delin You, Siliang Cheng, Zhukuan Yang, Dong-Lei Chen, Z. Jeffrey Nanjing Agr Univ State Key Lab Crop Genet & Germplasm Enhancement 1 Weigang Rd Nanjing 210095 Jiangsu Peoples R China Univ Texas Austin Inst Cellular & Mol Biol Dept Mol Biosci Austin TX 78712 USA Univ Texas Austin Ctr Computat Biol & Bioinformat Austin TX 78712 USA Chinese Acad Sci Inst Genet & Dev Biol 1 West Beichen Rd Beijing 100101 Peoples R China

Genetic imprinting refers to the unequal expression of paternal and maternal alleles of a gene in sexually reproducing organisms, including mammals and flowering plants. Although many imprinted genes have been identified in plants, the functions of these imprinted genes have remained largely uninvestigated. We report genome-wide analysis of gene expression, DNA methylation and small rnas in the rice endosperm and functional tests of five imprinted genes during seed development using Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated gene9 (CRISPR/Cas9) gene editing technology. In the rice endosperm, we identified 162 maternally expressed genes (MEGs) and 95 paternally expressed genes (PEGs), which were associated with miniature inverted-repeat transposable elements, imprinted differentially methylated loci and some 21-22 small interfering rnas (sirnas) and long noncoding rnas (lncrnas). Remarkably, one-third of MEGs and nearly one-half of PEGs were associated with grain yield quantitative trait loci. Most MEGs and some PEGs were expressed specifically in the endosperm. Disruption of two MEGs increased the amount of small starch granules and reduced grain and embryo size, whereas mutation of three PEGs reduced starch content and seed fertility. Our data indicate that both MEGs and PEGs in rice regulate nutrient metabolism and endosperm development, which optimize seed development and offspring fitness to facilitate parental-offspring coadaptation. These imprinted genes and mechanisms could be used to improve the grain yield of rice and other cereal crops.

关键词： DNA methylation epigenetics miniature inverted-repeat transposable element (MITE) noncoding rna rice seed development

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Small Nucleolar rna Host Gene 18 Acts as a Tumor Suppressor and a Diagnostic Indicator in Hepatocellular Carcinoma

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TECHNOLOGY IN CANCER RESEARCH & TREATMENT 2018年第17期17卷 1-8页

作者： Liu, Xue-Fang Thin, Khaing Zar Ming, Xin-Liang Shuo-Li Ping-Luo Man-Zhu Li, Nan-Di Tu, Jian-Cheng Wuhan Univ Zhongnan Hosp Dept Clin Lab Med Wuhan 430071 Hubei Peoples R China Wuhan Univ Zhongnan Hosp Ctr Gene Diag Wuhan 430071 Hubei Peoples R China

Background: noncoding rnas are crucial regulators acting as either tumor suppressor genes or oncogenes in human cancer progression. The aberrant expression of noncoding rnas has been confirmed in different kinds of cancers. Hepatocellular carcinoma is one of the most common malignant tumors worldwide, characterized by insidious onset, great malignancy, and high rates of recurrence and metastasis. Due to lack of early predictive markers, numerous patients are diagnosed in the late stages. As therapeutic options for advanced patients are quite limited, great efforts have been made to screen patients at early stages. A previous study reported that small nucleolar rna host gene 18 played crucial role in glioma. However, its functions and roles in hepatocellular carcinoma are unknown. Purpose: To explore its functional role and diagnostic value in hepatocellular carcinoma, we investigated its expression level. Methods: We performed real-time quantitative polymerase chain reaction in tumor tissues and adjacent non-cancerous tissues derived from patients with hepatocellular carcinoma as well as in plasma, including samples from the healthy control, patients with hepatitis B, cirrhosis, and hepatocellular carcinoma. Results: Small nucleolar rna host gene 18 was downregulated in liver tissues compared to paired adjacent noncancerous tissues (P < .0001). Meanwhile, plasma small nucleolar rna host gene 18 showed a relatively high sensitivity and specificity (75.61% and 73.49%) for distinguishing patients with hepatocellular carcinoma whose alpha-fetoprotein levels were below 200 ng/mL from the healthy controls. Conclusion: Our study suggested that small nucleolar rna host gene 18 might act as a tumor suppressor gene in hepatocellular carcinoma and potentially a diagnostic indicator to distinguish hepatocellular carcinoma from the healthy control and cirrhosis.

关键词： noncoding rna HCC SNHG18 tumor suppressor gene diagnostic marker

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rna-mediated gene fusion in mammalian cells

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2018年第52期115卷 E12295-E12304页

作者： Gupta, Sachin Kumar Luo, Liming Yen, Laising Baylor Coll Med Dept Pathol & Immunol Houston TX 77030 USA Baylor Coll Med Dept Mol & Cellular Biol Houston TX 77030 USA Baylor Coll Med Dan L Duncan Canc Ctr Houston TX 77030 USA

One of the hallmarks of cancer is the formation of oncogenic fusion genes as a result of chromosomal translocations. Fusion genes are presumed to form before fusion rna expression. However, studies have reported the presence of fusion rnas in individuals who were negative for chromosomal translocations. These observations give rise to "the cart before the horse" hypothesis, in which the genesis of a fusion rna precedes the fusion gene. The fusion rna then guides the genomic rearrangements that ultimately result in a gene fusion. However, rna-mediated genomic rearrangements in mammalian cells have never been demonstrated. Here we provide evidence that expression of a chimeric rna drives formation of a specified gene fusion via genomic rearrangement in mammalian cells. The process is: (i) specified by the sequence of chimeric rna involved, (ii) facilitated by physiological hormone levels, (iii) permissible regardless of intrachromosomal (TMPRSS2-ERG) or interchromosomal (TMPRSS2-ETV1) fusion, and (iv) can occur in normal cells before malignant transformation. We demonstrate that, contrary to "the cart before the horse" model, it is the antisense rather than sense chimeric rnas that effectively drive gene fusion, and that this disparity can be explained by transcriptional conflict. Furthermore, we identified an endogenous rna AZI1 that functions as the "initiator" rna to induce TMPRSS2-ERG fusion. rna-driven gene fusion demonstrated in this report provides important insight in early disease mechanisms, and could have fundamental implications in the biology of mammalian genome stability, as well as gene-editing technology via mechanisms native to mammalian cells.

关键词： gene fusion chimeric rna prostate cancer R-loop noncoding rna

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Circular rna: an emerging key player in rna world

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BRIEFINGS IN BIOINFORMATICS 2017年第4期18卷 547-557页

作者： Meng, Xianwen Li, Xue Zhang, Peijing Wang, Jingjing Zhou, Yincong Chen, Ming Zhejiang Univ Ming Chens Lab Hangzhou Zhejiang Peoples R China Zhejiang Univ Dept Bioinformat Coll Life Sci Hangzhou Zhejiang Peoples R China

Insights into the circular rna (circrna) exploration have revealed that they are abundant in eukaryotic transcriptomes. Diverse genomic regions can generate different types of rna circles, implying their diversity. Covalently closed loop structures elevate the stability of this new type of noncoding rna. High-throughput sequencing analyses suggest that circrnas exhibit tissue-and developmental-specific expression, indicating that they may play crucial roles in multiple cellular processes. Strikingly, several circrnas could function as microrna sponges and regulate gene transcription, highlighting a new class of important regulators. Here, we review the recent advances in knowledge of endogenous circrna biogenesis, properties and functions. We further discuss the current findings about circrnas in human diseases. In plants, the roles of circrnas remain a mystery. Online resources and bioinformatics identification of circrnas are essential for the analysis of circrna biology, although different strategies yield divergent results. The understanding of circrna functions remains limited;however, circrnas are enriching the rna world, acting as an emerging key player.

关键词： circular rna noncoding rna high-throughput sequencing mirna sponge human disease bioinformatics identification

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Transcriptome of blood cells as a reservoir of cardiovascular biomarkers

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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017年第1期1864卷 209-216页

作者： Devaux, Yvan Luxembourg Inst Hlth Cardiovasc Res Unit L-1526 Luxembourg Luxembourg Cardiolinc Network Www Cardiolinc Org Luxembourg Luxembourg

Biomarkers have the potential to move personalized medicine a step forward for the patients' benefit. Blood is a non-invasive source of biomarkers. The cell-free compartment of the blood has traditionally been used to search for biomarkers and currently used cardiovascular biomarkers are mainly measured in plasma or serum fractions. While most of these biomarkers are proteins, very few belong to the rna family due to methodological constraints inherent to the assessment of rnas. Over the past decade, technological developments have overcome these constraints and have allowed the assessment of rnas in blood cells. Thus, the search for novel cardiovascular biomarkers among rnas expressed in blood cells has emerged. This review highlights the potential of the transcriptome of blood cells to be used as a reservoir of novel cardiovascular biomarkers. First, the benefit of using biomarkers for personalized medicine is introduced. The focus is on the rna family of biomarkers, both coding and non-coding. The value of systems-based approaches for biomarker discovery is discussed. Then, the current knowledge of the use of blood cells' transcriptome for biomarker discovery is reviewed. Recent technological developments that have facilitated the study of the transcriptome of blood cells are presented. Further axes of developments are proposed to bring rna-based biomarkers to clinical application. Lastly, some directions for future work are presented. (C) 2016 Elsevier B.V. All rights reserved.

关键词： Biomarker Cardiovascular disease rna Transcriptomics noncoding rna Personalized medicine

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The rnas of rna-directed DNA methylation

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Biochimica et Biophysica Acta-Gene Regulatory Mechanisms 2017年第1期1860卷 140-148页

作者： Wendte, Jered M. Pikaard, Craig S. Indiana Univ Dept Biol 915 E Third St Bloomington IN 47405 USA Indiana Univ Dept Mol & Cellular Biochem 915 E Third St Bloomington IN 47405 USA Indiana Univ Howard Hughes Med Inst Bloomington IN 47405 USA

rna-directed chromatin modification that includes cytosine methylation silences transposable elements in both plants and mammals, contributing to genome defense and stability. In Arabidopsis thaliana, most rna-directed DNA methylation (RdDM) is guided by small rnas derived from double-stranded precursors synthesized at cytosine-methylated loci by nuclear multisubunit rna Polymerase IV (Pol IV), in close partnership with the rna-dependent rna polymerase, RDR2. These small rnas help keep transposons transcriptionally inactive. However, if transposons escape silencing, and are transcribed by multisubunit rna polymerase II (Pol II), their mrnas can be recognized and degraded, generating small rnas that can also guide initial DNA methylation, thereby enabling subsequent Pol IV-RDR2 recruitment. In both pathways, the small rnas find their target sites by interacting with longer noncoding rnas synthesized by multisubunit rna Polymerase V (Pol V). Despite a decade of progress, numerous questions remain concerning the initiation, synthesis, processing, size and features of the rnas that drive RdDM. Here, we review recent insights, questions and controversies concerning rnas produced by Pols IV and V, and their functions in RdDM. We also provide new data concerning Pol V transcript 5' and 3' ends. This article is part of a Special Issue entitled: Plant Gene Regulatory Mechanisms and Networks. This article is part of a Special Issue entitled: Plant Gene Regulatory Mechanisms and Networks, edited by Dr. Erich Grotewold and Dr. Nathan Springer. (C) 2016 Elsevier B.V. All rights reserved.

关键词： rna silencing Epigenetic regulation Cytosine methylation Chromatin modification Gene regulation noncoding rna

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The EGLN-HIF O₂-Sensing System: Multiple Inputs and Feedbacks

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MOLECULAR CELL 2017年第6期66卷 772-779页

作者： Ivan, Mircea Kaelin, William G., Jr. Indiana Univ Sch Med Dept Med Indianapolis IN 46202 USA Indiana Univ Sch Med Dept Microbiol & Immunol Indianapolis IN 46202 USA Howard Hughes Med Inst Boston MA 02215 USA Dana Farber Canc Inst Boston MA 02215 USA Harvard Med Sch Brigham & Womens Hosp Boston MA 02215 USA

The EGLN (also called PHD) prolyl hydroxylase enzymes and their canonical targets, the HIF alpha subunits, represent the core of an ancient oxygen-monitoring machinery used by metazoans. In this review, we highlight recent progress in understanding the overlapping versus specific roles of EGLN enzymes and HIF isoforms and discuss how feedback loops based on recently identified noncoding rnas introduce additional layers of complexity to the hypoxic response. Based on novel interactions identified upstream and downstream of EGLNs, an integrated network connecting oxygen-sensing functions to metabolic and signaling pathways is gradually emerging with broad therapeutic implications.

关键词： EGLN HIF1α HIF2α PHD hypoxia lncrna metabolism mirna noncoding rna oxygen

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A Network of noncoding Regulatory rnas Acts in the Mammalian Brain

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CELL 2018年第2期174卷 350-+页

作者： Kleaveland, Benjamin Shi, Charlie Y. Stefano, Joanna Bartel, David P. Howard Hughes Med Inst Cambridge MA 02142 USA Whitehead Inst Biomed Res Cambridge MA 02142 USA MIT Dept Biol Cambridge MA 02139 USA Massachusetts Gen Hosp Dept Pathol Boston MA 02114 USA

noncoding rnas (ncrnas) play increasingly appreciated gene-regulatory roles. Here, we describe a regulatory network centered on four ncrnas-a long ncrna, a circular rna, and two micrornasusing gene editing in mice to probe the molecular consequences of disrupting key components of this network. The long ncrna Cyrano uses an extensively paired site to miR-7 to trigger destruction of this microrna. Cyrano-directed miR-7 degradation is much more effective than previously described examples of target-directed microrna degradation, which come primarily from studies of artificial and viral rnas. By reducing miR-7 levels, Cyrano prevents repression of miR-7-targeted mrnas and enables accumulation of Cdr1as, a circular rna known to regulate neuronal activity. Without Cyrano, excess miR-7 causes cytoplasmic destruction of Cdr1as in neurons, in part through enhanced slicing of Cdr1as by a second mirna, miR-671. Thus, several types of ncrnas can collaborate to establish a sophisticated regulatory network.

关键词： TDMD circrna lncrna knockout mammalian gene regulation mirna knockout mirna tailing mirna target-site disruption mirna trimming noncoding rna regulatory network

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