长链非编码RNA（lncRNAs）的研究策略及其在中枢神经退行性疾病中的研究进展

神经药理学报 ›› 2014, Vol. 4 ›› Issue (4): 42-49.

长链非编码RNA（lncRNAs）的研究策略及其在中枢神经退行性疾病中的研究进展

张钊，楚世峰，黄惠勇，陈乃宏

1.中国医学科学院，药物研究所 & 神经科学中心，天然药物活性物质与功能国家重点实验室，北京，100050，中国
2.湖南中医药大学，长沙，410000，中国

出版日期:2014-08-26 发布日期:2015-01-20
通讯作者: 陈乃宏，男，研究员，博士生导师，研究方向：神经系统疾患创新药物开发及作用机制，Tel/Fax: 010-63165177, E-mail: chennh@imm.ac.cn
作者简介:张钊，女，博士生，研究方向：神经药理学和神经分子生物学，Tel/Fax: 010-63165182, E-mail：zhangzhao@imm.ac.cn
基金资助:
国家自然科学基金项目（No. 81274122、No. 81102831、No. 81273629、No. 21272278、No. 81473376、No.U1402221），国家“重大新药创制”科技重大专项（No. 2012ZX09301002-004、No. 2012ZX09301002-001-002），国家高技术研究发展计划（863 计划）（No. 2012AA020303），教育部博士点基金重点项目（No. 20121106130001），北京市自然科学基金（No. 7131013、No. 7142115），新药作用机制研究与药效评价北京市重点实验室资助项目（No. BZ0150），协和青年基金和中央高校基本科研业务费专项资金（No. 3332013157）

Long Noncoding RNAs：Research Strategies and Progresses in Neurodegenerative Diseases

Zhang Zhao, Chu Shi-feng, Huang Hui-yong, Chen Nai-hong

1 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Neuroscience Center, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
2 Hunan University Of Chinese Medicine

Online:2014-08-26 Published:2015-01-20
Contact: 陈乃宏，男，研究员，博士生导师，研究方向：神经系统疾患创新药物开发及作用机制，Tel/Fax: 010-63165177, E-mail: chennh@imm.ac.cn
About author:张钊，女，博士生，研究方向：神经药理学和神经分子生物学，Tel/Fax: 010-63165182, E-mail：zhangzhao@imm.ac.cn
Supported by:
国家自然科学基金项目（No. 81274122、No. 81102831、No. 81273629、No. 21272278、No. 81473376、No.U1402221），国家“重大新药创制”科技重大专项（No. 2012ZX09301002-004、No. 2012ZX09301002-001-002），国家高技术研究发展计划（863 计划）（No. 2012AA020303），教育部博士点基金重点项目（No. 20121106130001），北京市自然科学基金（No. 7131013、No. 7142115），新药作用机制研究与药效评价北京市重点实验室资助项目（No. BZ0150），协和青年基金和中央高校基本科研业务费专项资金（No. 3332013157）

摘要/Abstract

摘要： 长链非编码RNA（lncRNAs）是真核细胞中转录本长度超过200 nt的非编码RNA。近年来的研究表明lncRNAs具有一系列的重要功能，包括影响转录、RNA剪切、翻译、核因子转运、基因重排及染色质修饰等，lncRNAs的异常表达常与肿瘤、神经退行性疾病、心血管系统疾病等的发生发展密切相关，因此对lncRNAs的研究将有助于我们对机体生理病理反应的内在机制形成更为系统的认识。本文将就lncRNAs的研究策略及其在神经退行性疾病中的研究进展进行综述，以期为神经系统调控网络的建立及神经退行性疾病的防治提供新的思路。

关键词: 长链非编码RNA, 研究策略, 神经退行性疾病, 阿尔茨海默病, 帕金森氏病, 亨廷顿舞蹈症, 肌萎缩侧索硬化症

Abstract: Long noncoding RNAs (lncRNAs) are transcribed RNA molecules greater than 200 nucleotides in length. Nowadays, lncRNAs are found to have lots of functions including regulating transcription, post-transcriptional RNA processing, translation, nuclear factor transport, gene rearrangement and chromatin modification. Abnormal expressions of lncRNAs always come along with the pathogenesis of many diseases, such as cancer, neurodegenerative disorders, and cardiovascular disease. Thus a systematic and comprehensive profiling of lncRNA will help us to have a deeper understanding of the pathogenesis of the diseases. This article will focus on the research strategies of lncRNA and the latest progress in neurodegenerative diseases, which will contribute to the establishment of the regulation network of nervous system, and provide new ideas for the prevention of neurodegenerative diseases.

Key words: long noncoding RNAs, research strategy, neurodegenerative diseases, Alzheimer&, rsquo, s disease, Parkinson&, rsquo, s disease, Huntington&, rsquo, s disease, amyotrophic lateral sclerosis

中图分类号:

R964

张钊，楚世峰，黄惠勇，陈乃宏. 长链非编码RNA（lncRNAs）的研究策略及其在中枢神经退行性疾病中的研究进展[J]. 神经药理学报, 2014, 4(4): 42-49.

Zhang Zhao, Chu Shi-feng, Huang Hui-yong, Chen Nai-hong. Long Noncoding RNAs：Research Strategies and Progresses in Neurodegenerative Diseases[J]. Acta Neuropharmacologica, 2014, 4(4): 42-49.

参考文献

[1] The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome [J]. Nature, 2012, 489 (7414):57-74.

[2] Ryan J Taft, Ken C Pang, Timothy R Mercer, et al. Non-coding RNAs: regulators of disease [J]. J Pathology, 2010, 220 (2):126-39.

[3] Carolyn J Brown, Andrea Ballabio, James L Rupert, et al. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome [J]. Nature, 1991, 349 (6304):38-44.

[4] Marisa S Bartolomei, Sharon Zemel, Shirley M Tilghman. Parental imprinting of the mouse H19 gene [J]. Nature, 1991, 351 (6322):153-155.

[5] Okazaki Y, Furuno M, Kasukawa T, et al. Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs [J]. Nature, 2002, 420 (6915):563-573.

[6] Cristina Tufarelli, Jackie A Stanley, David Garrick, et al. Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease [J]. Nature Genetics, 2003, 34 (2):157-165.

[7] Rebecca A Chodroff, Leo Goodstadt, Tamara M Sirey, et al. Long noncoding RNA genes: conservation of sequence and brain expression among diverse amniotes [J]. Genome biology, 2010, 11 (7):R72.

[8] Yamini Arthanari, Christian Heintzen, Sam Griffiths-Jones, et al. Natural antisense transcripts and long non-coding RNA in Neurospora crassa [J]. PloS One, 2014, 9 (3):e91353.

[9] Chris P Ponting, Peter L Oliver, Wolf Reik. Evolution and functions of long noncoding RNAs [J]. Cell, 2009, 136 (4):629-641.

[10] Tim R Mercer, Dagmar Wilhelm, Marcel E Dinger, et al. Expression of distinct RNAs from 3' untranslated regions [J]. Nucleic Acids Res, 2011, 39 (6):2393-2403.

[11] Tiffany Hung, Yulei Wang, Michael F Lin, et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters [J]. Nature Genet, 2011, 43 (7):621-629.

[12] Ulf A Orom, Thomas Derrien, Malte Beringer, et al. Long noncoding RNAs with enhancer-like function in human cells [J]. Cell, 2010, 143 (1):46-58.

[13] Claus M Azzalin, Patrick Reichenbach, Lela Khoriauli, et al. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends [J]. Science, 2007, 318 (5851):798-801.

[14] Sara Massone, Irene Vassallo, Gloria Fiorino, et al. 17A, a novel non-coding RNA, regulates GABA B alternative splicing and signaling in response to inflammatory stimuli and in Alzheimer disease [J]. Neurobiology Dis, 2011, 41 (2):308-317.

[15] Bernard Delphine, Prasanth Kannanganattu V, Tripathi Vidisha, et al. A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression [J]. J EMBO, 2010, 29 (18):3082-3093.

[16] Ahmad M Khalil, Mitchell Guttman, Maite Huarte, et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression [J]. Proc Nat Acad Sci USA, 2009, 106 (28):11667-11672.

[17] Marcel E Dinger, Paulo P Amaral, Tim R Mercer, et al. Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation [J]. Genome Res, 2008, 18 (9):1433-1445.

[18] Miao-Chih Tsai, Ohad Manor, Wan Yue, et al. Long noncoding RNA as modular scaffold of histone modification complexes [J]. Science, 2010, 329 (5992):689-693.

[19] Chi C Gu, D C Rao, Gary Stormo, et al. Role of gene expression microarray analysis in finding complex disease genes [J]. Genetic Epidemiol, 2002, 23 (1):37-56.

[20] Tim R Mercer, Irfan A Qureshi, Solen Gokhan, et al. Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation [J]. BMC Neurosci, 2010, 11:14.

[21] Hitzemann R, Bottomly D, Darakjian P, et al. Genes, behavior and next-generation RNA sequencing [J]. Genes Brain Behav, 2013, 12 (1):1-12.

[22] Lin Ming-yan, Erika Pedrosa, Abhishek Shah, et al. RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders [J]. PloS One, 2011, 6 (9):e23356.

[23] Anna Esteve-Codina, Robert Kofler, Nicola Palmieri, et al. Exploring the gonad transcriptome of two extreme male pigs with RNA-seq [J]. BMC Gen, 2011, 12:552.

[24] Huang Qi-chao, Lin Biao-yang, Liu Han-qiang, et al. RNA-Seq analyses generate comprehensive transcriptomic landscape and reveal complex transcript patterns in hepatocellular carcinoma [J]. PloS One, 2011, 6 (10):e26168.

[25] Jae-Hyung Lee, Gao Chen, Peng Guang-dun, et al. Analysis of transcriptome complexity through RNA sequencing in normal and failing murine hearts [J]. Circulation Res, 2011, 109 (12):1332-1341.

[26] Masaaki Furuno, Ken C Pang, Noriko Ninomiya, et al. Clusters of internally primed transcripts reveal novel long noncoding RNAs [J]. PLoS Genet, 2006, 2 (4):e37.

[27] Radha Raman Pandey, Tanmoy Mondal, Faizaan Mohammad, et al. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation [J]. Molecular Cell, 2008, 32 (2):232-246.

[28] Ritu Jain, Tiffany Devine, Ajish D George, et al. RIP-Chip analysis: RNA-Binding Protein Immunoprecipitation-Microarray (Chip) Profiling [J]. Methods Mol Biol, 2011, 703:247-263.

[29] Zhao Jing, Toshiro K Ohsumi, Johnny T Kung, et al. Genome-wide identification of polycomb-associated RNAs by RIP-seq [J]. Molecular Cell, 2010, 40 (6):939-953.

[30] Liao Qi, Xiao Hui-xiao, Dechao Bu, et al. ncFANs: a web server for functional annotation of long non-coding RNAs [J]. Nucleic Acids Res, 2011, 39 (Web Server issue):W118-W124.

[31] Matteo Bellucci, Federico Agostini, Marianela Masin, et al. Predicting protein associations with long noncoding RNAs [J]. Nature Methods, 2011, 8 (6):444-445.

[32] Marcel E Dinger, Ken C Pang, Tim R Mercer, et al. NRED: a database of long noncoding RNA expression [J]. Nucleic Acids Rese, 2009, 37 (Database issue):D122-D126.

[33] Mohammad Ali Faghihi, Farzaneh Modarresi, Ahmad M Khalil, et al. Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase [J]. Nature Med, 2008, 14 (7):723-730.

[34] Mohammad Ali Faghihi, Zhang Ming, Huang Jia, et al. Evidence for natural antisense transcript-mediated inhibition of microRNA function [J]. Genome Biol, 2010, 11 (5):R56.

[35] Mus Ei, Patrick R Hof, Henri Tiedge. Dendritic BC200 RNA in aging and in Alzheimer's disease [J]. Proc Natl Acad Sci USA, 2007, 104 (25):10679-10684.

[36] Ivan Arisi, Mara D'Onofrio, Rossella Brandi, et al. Gene expression biomarkers in the brain of a mouse model for Alzheimer's disease: mining of microarray data by logic classification and feature selection [J]. J Alzheimer's Dis, 2011, 24 (4):721-738.

[37] Agnes Petit, Toshitaka Kawarai, Erwan Paitel, et al. Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations [J]. J Biol Chem, 2005, 280 (40):34025-34032.

[38] Camilla Scheele, Natasa Petrovic, Mohammad A Faghihi, et al. The human PINK1 locus is regulated in vivo by a non-coding natural antisense RNA during modulation of mitochondrial function [J]. BMC Genomics, 2007, 8:74.

[39] Masahito Shimojo. Huntingtin regulates RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin p150 Glued [J]. J Biol Chem, 2008, 283 (50):34880-34886.

[40] Rory Johnson, Nadine Richter, Ralf Jauch, et al. Human accelerated region 1 noncoding RNA is repressed by REST in Huntington's disease [J]. Physiological Genomics, 2010, 41 (3):269-274.

[41] Daniel W Chung, Dudnicki D Rudnicki, Yu Lan, et al. A natural antisense transcript at the Huntington's disease repeat locus regulates HTT expression [J]. Human Mol Genet, 2011, 20 (17):3467-3477.

[42] Mauro Cozzolino, Alberto Ferri, Cristiana Valle, et al. Mitochondria and ALS: implications from novel genes and pathways [J]. Molecular and Cellular Neurosciences, 2013, 55:44-9.

[43] Edward Pokrishevsky, Leslie I Grad, Masoud Yousefi, et al. Aberrant localization of FUS and TDP43 is associated with misfolding of SOD1 in amyotrophic lateral sclerosis [J]. PloS One, 2012, 7 (4):e35050.

[44] Yoshinori Nishimoto, Shinichi Nakagawa, Tetsuro Hirose, et al. The long non-coding RNA nuclear-enriched abundant transcript 1_2 induces paraspeckle formation in the motor neuron during the early phase of amyotrophic lateral sclerosis [J]. Molecular Brain, 2013, 6:31.

[45] George L Lee, Albert Dobi, Shiv Srivastava. Prostate cancer: diagnostic performance of the PCA3 urine test [J]. Nature Reviews Urology, 2011, 8 (3):123-124.

[46] Aya Mizrahi, Abraham Czerniak, Tally Levy, et al. Development of targeted therapy for ovarian cancer mediated by a plasmid expressing diphtheria toxin under the control of H19 regulatory sequences [J]. J Transl Med, 2009, 7:69.