lncRNA生物学功能研究进展
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摘要
长链非编码RNA(long non-coding RNA,lncRNA)是缺乏开放阅读框架,长度约为200 nt～100 000 bp,且不编码蛋白质的转录本。lncRNA的表达受到发育调控,具有组织及细胞特异性。目前认为,lncRNA执行重要的生物学功能,涉及转录调控、细胞内物质运输和染色体重塑,参与细胞分化、生长发育、应激反应和疾病发生发展等多种生物学进程。本文在介绍lncRNA的特征、分类、调控机制的基础上,重点对lncRNA的生物学功能进行综述。
Long non-coding RNAs(lncRNA)are transcripts without open reading frames,which are generally 200 nt to100 kb in length and do not encode proteins. The expression of lncRNA is regulated by development and has tissue and cell specificities. It is currently believed that lncRNAs perform important biological functions involving various biological processes such as transcriptional regulation,intracellular trafficking of substances and chromosomal remodeling,and participate in cell differentiation,growth and development,stress response and disease development. On the basis of introducing the characteristics,classification and regulation mechanism of lncRNA,this paper reviews the biological function of lncRNA.
Long non-coding RNAs(lncRNA)are transcripts without open reading frames,which are generally 200 nt to100 kb in length and do not encode proteins. The expression of lncRNA is regulated by development and has tissue and cell specificities. It is currently believed that lncRNAs perform important biological functions involving various biological processes such as transcriptional regulation,intracellular trafficking of substances and chromosomal remodeling,and participate in cell differentiation,growth and development,stress response and disease development. On the basis of introducing the characteristics,classification and regulation mechanism of lncRNA,this paper reviews the biological function of lncRNA.
引文
[1] JALALI S,GANDHI S,SCARIA V. Navigating the dynamic landscape of long noncoding RNA and protein-coding gene annotations in GENCODE[J]. Hum Genomics,2016,10(1):35.
[2] CHENG J,KAPRANOV P,DRENKOW J,et al. Transcriptional maps of human chromosomes at 5-nucleotide resolution[J]. Science,2005,308(5725):1149-1154.
[3] RINN J L,KERTESZ M,WANG J K,et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs[J]. Cell,2007,129(7):1311-1323.
[4] ESPINOZA C A,GOODRICH J A,KUGEL J F. Characterization of the structure,function,and mechanism of B2 RNA,an ncRNA repressor of RNA polymerase II transcription[J]. RNA,2007,13(4):583-596.
[5] KOUR S,RATH P C. Long noncoding RNAs in aging and agerelated diseases[J]. Aging Res Rev,2016,26(1):1-21.
[6] Kaessmann H. Origins,evolution,and phenotypic impact of new genes[J]. Genome Res,2010,20(10):1313-1326.
[7] SMITH J E,ALVAREZ-DOMINGUEZ J R,KLINE N,et al.Translation of small open reading frames within unannotated RNA transcripts in Saccharomyces cerevisiae[J]. Cell Rep,2014,7(6):1858-1866.
[8] SIGOVA A A,MULLEN A C,MOLINIE B,et al. Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells[J]. Proc Natl Acad Sci USA,2013,110(8):2876-2881.
[9] SUN M,KRAUS W L. From discovery to function:the expanding roles of long noncoding RNAs in physiology and disease[J]. Endocr Rev,2015,36(1):25-64.
[10] MOHAMMAD F,PANDEY R R,NAGANO T,et al. Kcnq1ot1/Lit1 noncoding RNA mediates transcriptional silencing by targeting to the perinucleolar region[J]. Mol Cell Biol,2008,28(11):3713-3728.
[11] ZEARFOSS N R,CHAN A P,KLOC M,et al. Identification of new Xlsirt family members in the Xenopus laevis oocyte[J].Mech Dev,2003,120(4):503-509.
[12] WUTZ A,RASMUSSEN T P,JAENISCH R. Chromosomal silencing and localization are mediated by different domains of Xist RNA[J]. Nat Genet,2002,30(2):167-174.
[13] S?RENSEN K P,THOMASSEN M,TAN Q,et al. Long noncoding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer[J]. Breast Cancer Res Treat,2013,142(3):529-536.
[14] REIS E M,NAKAYA H I,LOURO R,et al. Antisense intro-nic non-coding RNA levels correlate to the degree of tumor differentiation in prostate cancer[J]. Oncogene,2004,23(39):6684-6692.
[15] ADELMAN K,EGAN E. Non-coding RNA:more uses for genomic junk[J]. Nature,2017,543(7644):183-185.
[16] GOMEZ J A,WAPINSKI O L,YANG Y W,et al. The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-γlocus[J]. Cell,2013,152(4):743-754.
[17] KAMBARA H,NIAZI F,KOSTADINOVA L,et al. Negative regulation of the interferon response by an interferon-induced long non-coding RNA[J]. Nucleic Acids Res,2014,42(16):10668-10680.
[18] OUYANG J,ZHU X,CHEN Y,et al. NRAV,a long noncoding RNA,modulates antiviral responses through suppression of interferon-stimulated gene transcription[J]. Cell Host Micro-be,2014,16(5):616-626.
[19] AYNAUD M M,SUSP魬NE R,VIDALAIN P O,et al. Human Tribbles 3 protects nuclear DNA from cytidine deamination by APOBEC3A[J]. J Biol Chem,2012,287(46):39182-39192.
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[21] RAPICAVOLI N A,QU K,ZHANG J,et al. A mammalian pseudogene lncRNA at the interface of inflammation and antiinflammatory therapeutics[J]. Elife,2013,2:e00762. doi:10.7554/eLife.00762.
[22] HU G,TANG Q,SHARMA S,et al. Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation[J]. Nat Immunol,2013,14(11):1190-1198.
[23] MURET K,KLOPP C,WUCHER V,et al. Long noncoding RNA repertoire in chicken liver and adipose tissue[J]. Genet Sel Evol,2017,49(1):6. doi:10.1186/s12711-016-0275-0.
[24] QIAN T M,GAO R,YU B,et al. Altered lncRNA expression following sciatic nerve resection in rats[J]. Med J Commun,2012,26(4):306-308,315.(in Chinese)钱天梅,高蓉,于彬,等.大鼠坐骨神经缺损后背根神经节组织lncRNA表达变化[J].交通医学,2012,26(4):306-308,315.
[25] FENG J,BI C,CLARK B S,et al. The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator[J]. Genes&Dev,2006,20(11):1470-1484.
[26] HALLEY P,KADAKKUZHA B M,FAGHIHI M A,et al. Regulation of the apolipoprotein gene cluster by a long noncoding RNA[J]. Cell Rep,2014,6(1):222-230.
[27] SHORE A N,KABOTYANSKI E B,ROARTY K,et al. Pregnancy-induced noncoding RNA(PINC)associates with polycomb repressive complex 2 and regulates mammary epithelial differentiation[J]. PLoS Genet,2012,8(7):e1002840. doi:10.1371/journal.pgen.1002840.
[28] CALIN G A,LIU C G,FERRACIN M,et al. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas[J]. Cancer Cell,2007,12(3):215-229.
[29] INGOLIA N T,LAREAU L F,WEISSMAN J S. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes[J]. Cell,2011,147(4):789-802.
[30] RASOOL M,MALIK A,ZAHID S,et al. Non-coding RNAs in cancer diagnosis and therapy[J]. Noncoding RNA Res,2016,1(1):69-76.
[31] ZHENG Z G,HAN J,LIAO J H. The expression of lncRNA MEG3 and its relationship with prognosis of small cell lung cancer[J]. Chin Clin Oncol,2017,22(1):17-21.(in Chinese)郑志刚,韩军,廖继红.小细胞肺癌组织中lncRNA MEG3的表达及其与预后关系的研究[J].临床肿瘤学杂志,2017,22(1):17-21.
[32] GAO Y F,WANG Z B,ZHU T,et al. A critical overview of long non-coding RNA in glioma etiology 2016:an update[J].Tumor Biol,2016,37(11):14403-14413.
[33] MATSUMOTO A,PASUT A,MATSUMOTO M,et al. m TORC1and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide[J]. Nature,2017,541(7636):228-232.
[34] HEERY R,FINN S P,CUFFE S,et al. Long non-coding RNAs:key regulators of epithelial-mesenchymal transition,tumour drug resistance and cancer stem cells[J]. Cancers(Basel),2017,9(4):pii:E38. doi:10.3390/cancers9040038.
[35] HAN F,WANG C,WANG Y,et al. Long noncoding RNA ATB promotes osteosarcoma cell proliferation,migration and invasion by suppressing miR-200s[J]. Am J Cancer Res,2017,7(4):770-783.
[36] TANI H,ONUMA Y,ITO Y,et al. Long non-coding RNAs as surrogate indicators for chemical stress responses in human-induced pluripotent stem cells[J]. PLoS One,2014,9(8):e1062-82. doi:10.1371/journal.pone.0106282.
[37] QUAN H Y,FAN Q Q,WANG L. Expression profile and bioinformatics studies of long noncoding RNA in mouse embryonic fibroblasts under endoplasmic reticulum[J]. J Med Res,2015,44(4):61-66.(in Chinese)全弘扬,樊倩倩,王林.小鼠胚胎成纤维细胞内质网应激反应中的长链非编码RNA表达谱及生物信息学研究[J].医学研究杂志,2015,44(4):61-66.
[38] KINO T,HURT D E,ICHIJO T,et al. Noncoding RNA gas5 is a growth arrest-and starvation-associated repressor of the glucocorticoid receptor[J]. Sci Signal,2010,3(107):ra8.doi:10.1126/scisignal.2000568.
[39] MARINER P D,WALTERS R D,ESPINOZA C A,et al. Human Alu RNA is a modular transacting repressor of m RNA transcription during heat shock[J]. Mol Cell,2008,29(4):499-509.
[40] RASOOL M,MALIK A,ZAHID S,et al. Non-coding RNAs in cancer diagnosis and therapy[J]. Noncoding RNA Res,2016,1(1):69-76.
[41] LIN R,MAEDA S,LIU C,et al. A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas[J]. Oncogene,2007,26(6):851-868.
[42] QIAO L. LncRNA AK054386 regulates the endoplasmic reticulum stress in the ischemia-reperfusion injury of hepatocyte:by acting as endogenous sponge of miR-199a-5p[D]. Shanghai:The Second Military Medical University,2016.(in Chinese)乔亮. LncRNA AK054386吸附miR-199a-5p在肝脏IRI中对内质网应激的调控作用[D].上海:第二军医大学,2016.
[43]付琳晴.基于RNA二级结构的调控玉米干旱应激响应lncRNA特征识别算法研究[D].吉林长春:吉林大学,2017.
[2] CHENG J,KAPRANOV P,DRENKOW J,et al. Transcriptional maps of human chromosomes at 5-nucleotide resolution[J]. Science,2005,308(5725):1149-1154.
[3] RINN J L,KERTESZ M,WANG J K,et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs[J]. Cell,2007,129(7):1311-1323.
[4] ESPINOZA C A,GOODRICH J A,KUGEL J F. Characterization of the structure,function,and mechanism of B2 RNA,an ncRNA repressor of RNA polymerase II transcription[J]. RNA,2007,13(4):583-596.
[5] KOUR S,RATH P C. Long noncoding RNAs in aging and agerelated diseases[J]. Aging Res Rev,2016,26(1):1-21.
[6] Kaessmann H. Origins,evolution,and phenotypic impact of new genes[J]. Genome Res,2010,20(10):1313-1326.
[7] SMITH J E,ALVAREZ-DOMINGUEZ J R,KLINE N,et al.Translation of small open reading frames within unannotated RNA transcripts in Saccharomyces cerevisiae[J]. Cell Rep,2014,7(6):1858-1866.
[8] SIGOVA A A,MULLEN A C,MOLINIE B,et al. Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells[J]. Proc Natl Acad Sci USA,2013,110(8):2876-2881.
[9] SUN M,KRAUS W L. From discovery to function:the expanding roles of long noncoding RNAs in physiology and disease[J]. Endocr Rev,2015,36(1):25-64.
[10] MOHAMMAD F,PANDEY R R,NAGANO T,et al. Kcnq1ot1/Lit1 noncoding RNA mediates transcriptional silencing by targeting to the perinucleolar region[J]. Mol Cell Biol,2008,28(11):3713-3728.
[11] ZEARFOSS N R,CHAN A P,KLOC M,et al. Identification of new Xlsirt family members in the Xenopus laevis oocyte[J].Mech Dev,2003,120(4):503-509.
[12] WUTZ A,RASMUSSEN T P,JAENISCH R. Chromosomal silencing and localization are mediated by different domains of Xist RNA[J]. Nat Genet,2002,30(2):167-174.
[13] S?RENSEN K P,THOMASSEN M,TAN Q,et al. Long noncoding RNA HOTAIR is an independent prognostic marker of metastasis in estrogen receptor-positive primary breast cancer[J]. Breast Cancer Res Treat,2013,142(3):529-536.
[14] REIS E M,NAKAYA H I,LOURO R,et al. Antisense intro-nic non-coding RNA levels correlate to the degree of tumor differentiation in prostate cancer[J]. Oncogene,2004,23(39):6684-6692.
[15] ADELMAN K,EGAN E. Non-coding RNA:more uses for genomic junk[J]. Nature,2017,543(7644):183-185.
[16] GOMEZ J A,WAPINSKI O L,YANG Y W,et al. The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-γlocus[J]. Cell,2013,152(4):743-754.
[17] KAMBARA H,NIAZI F,KOSTADINOVA L,et al. Negative regulation of the interferon response by an interferon-induced long non-coding RNA[J]. Nucleic Acids Res,2014,42(16):10668-10680.
[18] OUYANG J,ZHU X,CHEN Y,et al. NRAV,a long noncoding RNA,modulates antiviral responses through suppression of interferon-stimulated gene transcription[J]. Cell Host Micro-be,2014,16(5):616-626.
[19] AYNAUD M M,SUSP魬NE R,VIDALAIN P O,et al. Human Tribbles 3 protects nuclear DNA from cytidine deamination by APOBEC3A[J]. J Biol Chem,2012,287(46):39182-39192.
[20] BOND A M,VANGOMPEL M J,SAMETSKY E A,et al. Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry[J]. Nat Neurosci,2009,12(8):1020-1027.
[21] RAPICAVOLI N A,QU K,ZHANG J,et al. A mammalian pseudogene lncRNA at the interface of inflammation and antiinflammatory therapeutics[J]. Elife,2013,2:e00762. doi:10.7554/eLife.00762.
[22] HU G,TANG Q,SHARMA S,et al. Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation[J]. Nat Immunol,2013,14(11):1190-1198.
[23] MURET K,KLOPP C,WUCHER V,et al. Long noncoding RNA repertoire in chicken liver and adipose tissue[J]. Genet Sel Evol,2017,49(1):6. doi:10.1186/s12711-016-0275-0.
[24] QIAN T M,GAO R,YU B,et al. Altered lncRNA expression following sciatic nerve resection in rats[J]. Med J Commun,2012,26(4):306-308,315.(in Chinese)钱天梅,高蓉,于彬,等.大鼠坐骨神经缺损后背根神经节组织lncRNA表达变化[J].交通医学,2012,26(4):306-308,315.
[25] FENG J,BI C,CLARK B S,et al. The Evf-2 noncoding RNA is transcribed from the Dlx-5/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator[J]. Genes&Dev,2006,20(11):1470-1484.
[26] HALLEY P,KADAKKUZHA B M,FAGHIHI M A,et al. Regulation of the apolipoprotein gene cluster by a long noncoding RNA[J]. Cell Rep,2014,6(1):222-230.
[27] SHORE A N,KABOTYANSKI E B,ROARTY K,et al. Pregnancy-induced noncoding RNA(PINC)associates with polycomb repressive complex 2 and regulates mammary epithelial differentiation[J]. PLoS Genet,2012,8(7):e1002840. doi:10.1371/journal.pgen.1002840.
[28] CALIN G A,LIU C G,FERRACIN M,et al. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas[J]. Cancer Cell,2007,12(3):215-229.
[29] INGOLIA N T,LAREAU L F,WEISSMAN J S. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes[J]. Cell,2011,147(4):789-802.
[30] RASOOL M,MALIK A,ZAHID S,et al. Non-coding RNAs in cancer diagnosis and therapy[J]. Noncoding RNA Res,2016,1(1):69-76.
[31] ZHENG Z G,HAN J,LIAO J H. The expression of lncRNA MEG3 and its relationship with prognosis of small cell lung cancer[J]. Chin Clin Oncol,2017,22(1):17-21.(in Chinese)郑志刚,韩军,廖继红.小细胞肺癌组织中lncRNA MEG3的表达及其与预后关系的研究[J].临床肿瘤学杂志,2017,22(1):17-21.
[32] GAO Y F,WANG Z B,ZHU T,et al. A critical overview of long non-coding RNA in glioma etiology 2016:an update[J].Tumor Biol,2016,37(11):14403-14413.
[33] MATSUMOTO A,PASUT A,MATSUMOTO M,et al. m TORC1and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide[J]. Nature,2017,541(7636):228-232.
[34] HEERY R,FINN S P,CUFFE S,et al. Long non-coding RNAs:key regulators of epithelial-mesenchymal transition,tumour drug resistance and cancer stem cells[J]. Cancers(Basel),2017,9(4):pii:E38. doi:10.3390/cancers9040038.
[35] HAN F,WANG C,WANG Y,et al. Long noncoding RNA ATB promotes osteosarcoma cell proliferation,migration and invasion by suppressing miR-200s[J]. Am J Cancer Res,2017,7(4):770-783.
[36] TANI H,ONUMA Y,ITO Y,et al. Long non-coding RNAs as surrogate indicators for chemical stress responses in human-induced pluripotent stem cells[J]. PLoS One,2014,9(8):e1062-82. doi:10.1371/journal.pone.0106282.
[37] QUAN H Y,FAN Q Q,WANG L. Expression profile and bioinformatics studies of long noncoding RNA in mouse embryonic fibroblasts under endoplasmic reticulum[J]. J Med Res,2015,44(4):61-66.(in Chinese)全弘扬,樊倩倩,王林.小鼠胚胎成纤维细胞内质网应激反应中的长链非编码RNA表达谱及生物信息学研究[J].医学研究杂志,2015,44(4):61-66.
[38] KINO T,HURT D E,ICHIJO T,et al. Noncoding RNA gas5 is a growth arrest-and starvation-associated repressor of the glucocorticoid receptor[J]. Sci Signal,2010,3(107):ra8.doi:10.1126/scisignal.2000568.
[39] MARINER P D,WALTERS R D,ESPINOZA C A,et al. Human Alu RNA is a modular transacting repressor of m RNA transcription during heat shock[J]. Mol Cell,2008,29(4):499-509.
[40] RASOOL M,MALIK A,ZAHID S,et al. Non-coding RNAs in cancer diagnosis and therapy[J]. Noncoding RNA Res,2016,1(1):69-76.
[41] LIN R,MAEDA S,LIU C,et al. A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas[J]. Oncogene,2007,26(6):851-868.
[42] QIAO L. LncRNA AK054386 regulates the endoplasmic reticulum stress in the ischemia-reperfusion injury of hepatocyte:by acting as endogenous sponge of miR-199a-5p[D]. Shanghai:The Second Military Medical University,2016.(in Chinese)乔亮. LncRNA AK054386吸附miR-199a-5p在肝脏IRI中对内质网应激的调控作用[D].上海:第二军医大学,2016.
[43]付琳晴.基于RNA二级结构的调控玉米干旱应激响应lncRNA特征识别算法研究[D].吉林长春:吉林大学,2017.