大數(shù)據(jù)與精準(zhǔn)醫(yī)學(xué)

1、大數(shù)據(jù)與精準(zhǔn)醫(yī)學(xué)大數(shù)據(jù)與精準(zhǔn)醫(yī)學(xué)Big Data and Precision MedicineBig Data and Precision Medicine報(bào)告報(bào)告人：人：陳潤(rùn)生陳潤(rùn)生“Lets Call it Precision Medicine!” “I want the country that eliminated polio and mapped the human genome to lead a new era of medicineone that delivers the right treatment at the right time. In some patients

2、with cystic fibrosis, this approach has reversed a disease once thought unstoppable. Tonight, Im launching a new Precision Medicine Initiative to bring us closer to curing diseases like cancer and diabetesand to give all of us access to the personalized information we need to keep ourselves and our

3、families healthier.”Jan. 20, 2015 健康科學(xué)的發(fā)展: 轉(zhuǎn)化醫(yī)學(xué) 個(gè)體化醫(yī)學(xué) 精準(zhǔn)醫(yī)學(xué) 精準(zhǔn)診斷和精準(zhǔn)治療精準(zhǔn)診斷和精準(zhǔn)治療本質(zhì)性轉(zhuǎn)變: 從診斷治療到健康保障 精準(zhǔn)預(yù)防精準(zhǔn)預(yù)防 基于精準(zhǔn)醫(yī)學(xué)理念的個(gè)體化治療市場(chǎng)規(guī)模日益擴(kuò)大，基于精準(zhǔn)醫(yī)學(xué)理念的個(gè)體化治療市場(chǎng)規(guī)模日益擴(kuò)大，2018 年前全球市場(chǎng)規(guī)模將達(dá)到年前全球市場(chǎng)規(guī)模將達(dá)到2238 億美元億美元 世界衛(wèi)生組織（WHO）2014 年非傳染性疾病國(guó)家概況統(tǒng)計(jì)數(shù)據(jù)顯示，我國(guó)在2000-2012 年腫瘤、2 型糖尿病、心血管疾病這三種慢病死亡總數(shù)達(dá)近700 萬(wàn)，占所有死亡人數(shù)的70%，遠(yuǎn)高于全球平均（45%）和英美等發(fā)達(dá)國(guó)

4、家（57%-61%）；到2030 年我國(guó)阿爾茨海默病患者將達(dá)1200萬(wàn)。我國(guó)心血管疾病患者約有2.9 億人，每年約有350 萬(wàn)人死于心血管疾病，占總死亡原因的41%，高居死因榜首。 精準(zhǔn)醫(yī)學(xué)研究已成為新一輪國(guó)家科技競(jìng)爭(zhēng)和精準(zhǔn)醫(yī)學(xué)研究已成為新一輪國(guó)家科技競(jìng)爭(zhēng)和引領(lǐng)國(guó)際發(fā)展潮流的戰(zhàn)略制高點(diǎn)。引領(lǐng)國(guó)際發(fā)展潮流的戰(zhàn)略制高點(diǎn)。美國(guó)積極推動(dòng)精準(zhǔn)醫(yī)學(xué)的發(fā)展，將其上升為國(guó)家戰(zhàn)略；歐盟以精準(zhǔn)醫(yī)學(xué)理念指導(dǎo)其創(chuàng)新藥物二期計(jì)劃；英國(guó)開(kāi)展十萬(wàn)人測(cè)序計(jì)劃并成立精確癌癥研究所；日本將精準(zhǔn)醫(yī)學(xué)相關(guān)內(nèi)容列入科技創(chuàng)新計(jì)劃中。這標(biāo)志著國(guó)際上在基因資源利用、新藥靶點(diǎn)發(fā)現(xiàn)、新的診斷治療方法開(kāi)發(fā)、生物醫(yī)藥新產(chǎn)品研發(fā)等的競(jìng)爭(zhēng)進(jìn)入新的階段，

5、對(duì)我國(guó)生物醫(yī)藥與健康產(chǎn)業(yè)的發(fā)展形成嚴(yán)峻挑戰(zhàn)。 美國(guó)積極推動(dòng)精準(zhǔn)醫(yī)學(xué)的發(fā)展 2011 年，美國(guó)國(guó)家科學(xué)院研究理事會(huì)（NRC）發(fā)布了題為“邁向精準(zhǔn)醫(yī)學(xué)：構(gòu)建生物醫(yī)學(xué)研究知識(shí)網(wǎng)絡(luò)和新的疾病分類(lèi)體系”的報(bào)告，首次提出精準(zhǔn)醫(yī)學(xué)概念。2015 年，美國(guó)開(kāi)始啟動(dòng)精準(zhǔn)醫(yī)學(xué)研究計(jì)劃，標(biāo)志著精準(zhǔn)醫(yī)學(xué)上升為國(guó)家戰(zhàn)略。為了促進(jìn)精準(zhǔn)醫(yī)學(xué)的發(fā)展，美國(guó)國(guó)立衛(wèi)生研究院（NIH）在2015 財(cái)年、2016 財(cái)年預(yù)算中將精準(zhǔn)醫(yī)學(xué)作為重點(diǎn)領(lǐng)域進(jìn)行資助，計(jì)劃在2015年10 月開(kāi)始投入2.15 億美元啟動(dòng)精準(zhǔn)醫(yī)學(xué)計(jì)劃，首先進(jìn)行100 萬(wàn)人基因組測(cè)序，與美國(guó)生物庫(kù)中的數(shù)據(jù)信息聯(lián)合形成大型研發(fā)資源庫(kù)，作為全面加速生物醫(yī)學(xué)研發(fā)計(jì)劃的一部分

6、，助力開(kāi)發(fā)新一代藥物；啟動(dòng)了腫瘤基因組圖譜二期計(jì)劃（TCGA2），進(jìn)一步加大腫瘤機(jī)制研究和腫瘤治療個(gè)體化藥物研發(fā)的“精準(zhǔn)”性。在藥物開(kāi)發(fā)方面，2014 年美國(guó)NIH 和生物制藥公司聯(lián)合啟動(dòng)重大研究項(xiàng)目加速建立醫(yī)學(xué)合作AMP 計(jì)劃，旨在發(fā)展用于新的診斷和藥物開(kāi)發(fā)的疾病靶標(biāo)模型，專(zhuān)注于阿爾茨海默病、2 型糖尿病、自身免疫性疾病類(lèi)中的風(fēng)濕性關(guān)節(jié)炎和系統(tǒng)性紅斑狼瘡等三類(lèi)疾病的研究。 歐盟及成員國(guó)力推精準(zhǔn)醫(yī)學(xué)研究 2014 年3 月，歐盟發(fā)布創(chuàng)新藥物2 期計(jì)劃戰(zhàn)略研究議程（IMI2），其主題是實(shí)現(xiàn)精準(zhǔn)醫(yī)療，即正確的時(shí)機(jī)向正確的病人提供正確的預(yù)防治療措施。IMI2 將帶來(lái)新的工具、方法及預(yù)防和治療方案，（

7、直接或間接）促進(jìn)個(gè)體化醫(yī)療的發(fā)展。2012 年，英國(guó)宣布對(duì)患有癌癥及罕見(jiàn)疾病的十萬(wàn)英國(guó)人進(jìn)行全基因組測(cè)序，旨在根據(jù)基因組學(xué)和臨床數(shù)據(jù)為患者制定個(gè)性化療法。英國(guó)技術(shù)戰(zhàn)略委員會(huì)（TSB）還在2014 年建立了“精準(zhǔn)醫(yī)學(xué)孵化器”，幫助英國(guó)在該領(lǐng)域加快創(chuàng)新步伐；牛津大學(xué)已投入約1.5 億英鎊，成立精準(zhǔn)癌癥醫(yī)學(xué)研究所。法國(guó)早在2012 年就在“投資未來(lái)計(jì)劃”國(guó)家計(jì)劃中，出資1 億歐元資助個(gè)體化醫(yī)療項(xiàng)目。 日本將精準(zhǔn)醫(yī)學(xué)相關(guān)內(nèi)容列入科技創(chuàng)新計(jì)劃中 日本在2011 年實(shí)施的FANTOM計(jì)劃第五階段中投入1 億美元開(kāi)展功能基因組研究。在2014 科技創(chuàng)新計(jì)劃中將“定制醫(yī)學(xué)/基因組醫(yī)學(xué)”列為重點(diǎn)關(guān)注領(lǐng)域之一。計(jì)

8、劃在2015 年建立疾病的全基因組數(shù)據(jù)庫(kù)，識(shí)別日本人的標(biāo)準(zhǔn)基因序列及有助于疾病預(yù)后的基因，并利用基因數(shù)據(jù)對(duì)抗癲癇劑的副作用進(jìn)行預(yù)測(cè)性診斷。至2020-2030 年大幅度改善終身性疾?。ㄌ悄虿　⒅酗L(fēng)、心臟?。┑母深A(yù)效果；建立對(duì)癌變可能性及抗癌藥物的治療效果或副作用的預(yù)測(cè)性診斷方法；開(kāi)展針對(duì)抑郁癥和癡呆癥的臨床研究；開(kāi)發(fā)診斷和治療神經(jīng)肌肉疾病的診斷和治療方法。 產(chǎn)業(yè)化前景精準(zhǔn)醫(yī)學(xué)的發(fā)展將帶動(dòng)相關(guān)產(chǎn)業(yè)的快速發(fā)展，孕育巨大市場(chǎng)空間 首先，生物樣本和數(shù)據(jù)本身就具有市場(chǎng)價(jià)值。據(jù)統(tǒng)計(jì)，2015 年生物樣本庫(kù)市值將超過(guò)22.5 億美元。至2018 年生物大數(shù)據(jù)的市場(chǎng)總額將增長(zhǎng)至76 億美元，年復(fù)合增長(zhǎng)率達(dá)到7

9、1.6%。生物數(shù)據(jù)的商業(yè)價(jià)值已經(jīng)初步體現(xiàn)，2015 年1 月，羅氏制藥子公司Genentech 向美國(guó)基因測(cè)序公司23andMe 注資 6000 萬(wàn)美金，用于共享23andMe 收集的帕金森病患者的基因數(shù)據(jù)，并基于數(shù)據(jù)信息研發(fā)帕金森病的治療方案。 基因測(cè)序是精準(zhǔn)醫(yī)療產(chǎn)業(yè)的重要組成部分。來(lái)自BBC research的數(shù)據(jù)顯示，全球基因測(cè)序市場(chǎng)總量從2007 年的794.1 萬(wàn)美元增長(zhǎng)至2013 年的45 億美元，預(yù)計(jì)未來(lái)幾年全球市場(chǎng)仍將繼續(xù)保持快速增長(zhǎng)，2018 年達(dá)到117 億美元。 分子診斷是精準(zhǔn)醫(yī)療的另一重要子行業(yè)，已經(jīng)成為生物醫(yī)藥行業(yè)新熱點(diǎn)，據(jù)Marketsand Markets 公司估

10、測(cè)， 2018 年的全球市場(chǎng)市值將達(dá)到79 億美元，2013-2018 年間的復(fù)合年增長(zhǎng)率為9.7%。 基于精準(zhǔn)醫(yī)學(xué)理念的個(gè)體化治療市場(chǎng)規(guī)模日益擴(kuò)大，2018 年前全球市場(chǎng)規(guī)模將達(dá)到2238 億美元。美國(guó)十大商業(yè)保險(xiǎn)公司已將50 余項(xiàng)疾病個(gè)體化診療分子檢測(cè)項(xiàng)目列入醫(yī)療保險(xiǎn)。巨大市場(chǎng)空間吸引眾多醫(yī)藥公司開(kāi)展研發(fā)，目前已有多種個(gè)體化診療產(chǎn)品上市。 截至2013 年，美國(guó)FDA 已批準(zhǔn)了100 多種個(gè)體化藥物，重點(diǎn)關(guān)注癌癥和慢性疾病的個(gè)性化治療。 我國(guó)精準(zhǔn)醫(yī)學(xué)的發(fā)展目標(biāo) 以我國(guó)常見(jiàn)高發(fā)重大疾病及若干罕見(jiàn)病為切入點(diǎn)，構(gòu)建百萬(wàn)人級(jí)自然人群國(guó)家大型健康隊(duì)列和特定疾病隊(duì)列、多層次精準(zhǔn)醫(yī)療知識(shí)庫(kù)體系和生物醫(yī)學(xué)

11、大數(shù)據(jù)共享平臺(tái)，突破新一代生命組學(xué)技術(shù)和大數(shù)據(jù)分析技術(shù)，建立創(chuàng)新性的大規(guī)模研發(fā)疾病預(yù)警、診斷、治療與療效評(píng)價(jià)的生物標(biāo)志物、靶標(biāo)、制劑的實(shí)驗(yàn)和分析技術(shù)體系。 以臨床應(yīng)用為導(dǎo)向，形成重大疾病的風(fēng)險(xiǎn)評(píng)估、預(yù)測(cè)預(yù)警、早期篩查、分型分類(lèi)、個(gè)體化治療、療效和安全性預(yù)測(cè)及監(jiān)控等精準(zhǔn)防診治方案和臨床決策系統(tǒng)，建設(shè)中國(guó)人群典型疾病精準(zhǔn)醫(yī)療臨床方案的示范、應(yīng)用和推廣體系，推動(dòng)一批精準(zhǔn)治療藥物和分子檢測(cè)技術(shù)產(chǎn)品進(jìn)入國(guó)家醫(yī)保目錄，為顯著提升人口健康水平、減少無(wú)效和過(guò)度醫(yī)療、避免有害醫(yī)療、遏制醫(yī)療費(fèi)用支出快速增長(zhǎng)提供科技支撐，使精準(zhǔn)醫(yī)療成為經(jīng)濟(jì)社會(huì)發(fā)展新的增長(zhǎng)點(diǎn)。 轉(zhuǎn)變的基礎(chǔ): 1、 組學(xué): 基因組, 轉(zhuǎn)錄組,蛋白質(zhì)組

12、,代謝組. 大數(shù)據(jù):人群、隊(duì)列 是當(dāng)前國(guó)際兩大科學(xué)前沿的交匯 2、 基因型與表型的關(guān)聯(lián) 生物信息學(xué) 生物網(wǎng)絡(luò) 系統(tǒng)生物學(xué)在此基礎(chǔ)上融合臨床檢驗(yàn)、影像學(xué)等指標(biāo) 創(chuàng)新的機(jī)遇在哪里？ 挑戰(zhàn)的問(wèn)題又在哪里？ 一、基因組中的暗信息How many characters are in the “Heaven Book”? 3*109 10,000 books 1 book 100 pages 1 page 3,000 characters CCGGTCTCCCCGCCCGCGCGCGAAGTAAAGGCCCAGCGCAGCCCGCGCTCCTGCCCTGGGGCCTCGTCTTTCTCCAGGAAAACG

13、TGGACCGCTCTCCGCCGACAGTCTCTTCCACAGACCCCTGTCGCCTTCGCCCCCCGGTCTCTTCCGGTTCTGTCTTTTCGCTGGCTCGATACGAACAAGGAAGTCGCCCCCAGCGAGCCCCGGCTCCCCCAGGCAGAGGCGGCCCCGGGGGCGGAGTCAACGGCGGAGGCACGCCCTCTGTGAAAGGGCGGGGCATGCAAATTCGAAATGAAAGCCCGGGAACGCCGAAGAAGCACGGGTGTAAGATTTCCCTTTTCAAAGGCGGGAGAATAAGAAATCAGCCCGAGAGTGTAAGGGCGT

14、CAATAGCGCTGTGGACGAGACAGAGGGAATGGGGCAAGGAGCGAGGCTGGGGCTCTCACCGCGACTTGAATGTGGATGAGAGTGGGACGGTGACGGCGGGCGCGAAGGCGAGCGCATCGCTTCTCGGCCTTTTGGCTAAGATCAAGTGTAGTATCTGTTCTTATCAGTTTAATATCTGATACGTCCTCTATCCGAGGACAATATATTAAATGGATTGATCAATCCGCTTCAGCCTCCCGAGTAGCTGGGACTACAGACGGTGCCATCACGCCCAGCTCATTGTTGATTCCCGCCCCCTTG

15、GTAGAGACGGGATTCCGCTATATTGCCTGGGCTGGTGTCGAACTCATAGAACAAAGGATCCTCCCTCCTGGGCCTGGGCGTGGGCTCGCAAAACGCTGGGATTCCCGGATTACAGGCGGGCGCACCACACCAGGAGCAAACACTTCCGGTTTTAAAAATTCAGTTTGTGATTGGCTGTCATTCAGTATTATGCTAATTAAGCATGCCCGGTTTTAAACCTCTTAAAACAACTTTTAAAATTACCTTTCCACCTAAAACGTTAAAATTTGTCAAGTGATAATATTCGACAAGCTGTTATTG

16、CCAAACTATTTTCCTATTTGTTTCCTAATGGCATCGGAACTAGCGAAAGTTTCTCGCCATCAGTTAAAAGTTTGCGGCAGATGTAGACCTAGCAGAGGTGTGCGAGGAGGCCGTTAAGACTATACTTTCAGGGATCATTTCTATAGTGTGTTACTAGAGAAGTTTCTCTGAACGTGTAGAGCACCGAAAACCACGAGGAAGAGAGGTAGCGTTTTCATCGGGTTACCTAAGTGCAGTGTCCCCCCTGGCGCGCAATTGGGAACCCCACACGCGGTGTAGAAATATATTTTAAGGGCGCG

17、(1250 characters) The 17 December 2010 issue of Science includes special sections highlighting the Breakthrough of the Year and Insights of the Decade. Insights of the DecadeShining a Light on the Genomes Dark Matter The scope of this “dark genome” became apparent in 2001, when the human genome was

18、first published. Scientists expected to find as many as 100,000 genes packed into the 3 billion bases of human DNA; they were startled to learn that there were fewer than 35,000. (The current count is 21,000.) Protein-coding regions accounted for just 1.5% of the genome. Could the rest of our DNA re

19、ally just be junk? 1、基因組研究 Noncoding sequences: Sequences in genome, which are not coding for any proteins.How many persent of the human genome are noncoding sequences?More than 97%!Proportion of functional elements within genomes17%0.5% Drosophila85%2%13%E. coli70%2%28%Yeast S. cerevisiae1.5%0.5%98

20、%Human28%0.5%71%Nematode C. elegans0.5%0.01%Lunfish (dipnoi)Coding (protein) RNA Non-coding82%99.5%2、轉(zhuǎn)錄組研究The central dogmaFrom wikiThe central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transfer

21、red back from protein to either protein or nucleic acid. -?Francis Crick 基因組和轉(zhuǎn)錄 Genome and transcription (tiling array data)編碼蛋白序列 Protein coding sequence人 基因組的 2-3 %線蟲(chóng) 基因組的 25 %基因組的轉(zhuǎn)錄水平 Transcriptional activity人 基因組的 90 % (40-50X)線蟲(chóng) 基因組的 70 % (2-3X)絕大部分的轉(zhuǎn)錄產(chǎn)物是 非編碼RNA The majority of transcripts are

22、non-coding RNAs物種間最主要的差別也是 非編碼RNA The major differences among different organisms are ncRNAs基因組的轉(zhuǎn)錄情況 Transcriptional output/complexity3、非編碼RNA的功能研究X-inactivation is the mammalian dosage compensation mechanism, used to equalize X-linked gene dosage between male and female cells. Xist encodes a large,

23、 spliced, polyadenylated, noncoding RNA that is expressed exclusively from the otherwise inactive X chromosome. /pibs/faculty/panning.htmlBarbara Panning Lab Small RNA and RNA Interference(RNAi） In RNAi, dsRNA introduced into susceptible organisms is processed into 22 nucleotide (n

24、t) siRNAs. These 22 nt siRNAs subsequently bind to the homologous region of their target transcript and tag it for nuclease cleavage. Thus gene silencing is effected by destruction of the target mRNA. A novel class of small RNAs bind to MILI protein in mouse testesNATURE|Vol 442|13 July 2006 The sma

25、ll RNAs are 2631 nucleotides (nt) in lengthclearly distinct from the 2123 nt of microRNAs (miRNAs) or short interfering RNAs (siRNAs)and we refer to them as Piwi-interacting RNAs or piRNAs. /PLANTncRNAs/ Noncoding RNA in Plants The infectious agents of prion disease such as Creu

26、tzfeldtJakob disease are thought to be composed of protein, with no associated nucleic acids. But that may not be the end of the story. An experiment in a cell-free amplification system shows that unidentified host RNA molecules are required for efficient conversion of normal prion protein into its

27、pathogenic form. Interestingly, these RNA molecules are not present in invertebrate species. This points to a possible involvement of host-coded RNA in the pathogenesis of prion diseases, and also provides a simple way of increasing the sensitivity of diagnostic tests based on the PMCA (protein misf

28、olding cyclic amplification) method.Some examples about noncoding Some examples about noncoding RNAs and diseases RNAs and diseases Elevated expression of PCGEM1, a prostate-specific gene with cell growth-promoting function, is associated with high-risk prostate cancer patientsGyorgy Petrovics*,1, W

29、ei Zhang2, Mazen Makarem1, Jesse P Street1, Roger Connelly1, Leon Sun1, Isabell A Sesterhenn2, Vasantha Srikantan1, Judd W Moul1,3 and Shiv Srivastava1Oncogene (2004) 23, 605611 PCGEM1 is a novel, highly prostate tissue-specific,androgen-regulated gene. Here, we demonstrate thatPCGEM1 expression is

30、significantly higher in prostate cancer (CaP) cells of African-American men than in Caucasian-American men. PCGEM1 PCGEM1 appears to be a noncoding functional RNAappears to be a noncoding functional RNAgene (Srikantan gene (Srikantan et alet al., 2000)., 2000).His-1: A noncoding RNA implicated in mo

31、use leukemogenesisFan Xu, Molly McFarland and David S. Askew*Histol. Histopathol., 1999, 14, 235241. The His-1 gene is highly conserved among vertebrate species and is transcribed as a single spliced and polyadenylated cytoplasmic RNA that shares several features in common with the emerging class of

32、 untranslated RNAs. A role for the His-1 gene in neoplastic transformation was first indicated by the identification of transcriptionally activated His-1 genes in a series of mouse leukemias, and more recent studies with antisense His-1 RNAs suggest that His-1 is involved in an oncogenic pathway tha

33、t controls cell cycle progression. MALAT-1,MALAT-1, a novel noncoding RNA, and a novel noncoding RNA, and thymosin b4 predict metastasisthymosin b4 predict metastasis and and survival in early-stage non-small cell survival in early-stage non-small cell lung cancerlung cancerPing Ji1,5, Sven Diederic

34、hs1,5, Wenbing Wang1, Sebastian Bo ing1, Ralf Metzger2, Paul M Schneider2, Nicola Tidow3, Burkhard Brandt3, Horst Buerger4, Etmar Bulk1, Michael Thomas1,Wolfgang E Berdel1, Hubert Serve*,1 and Carsten Mu ller-Tidow*,1Oncogene (2003) 22, 8031Oncogene (2003) 22, 803180418041Evidence for evolutionarily

35、 conserved secondary structure in the H19 tumor suppressor RNAVeronica Juan, Chad Crain and Charles WilsonBREAKTHROUGH OF THE YEAR(2001): Science celebrates nine other areas in which important findings were reported this year, from subatomic to atmospheric and beyond.First runner-up: RNA ascending.

36、Short RNAs clearly play important biological roles. Dozens of the molecules are now known to exist in the nematode and fruit fly. The coding for these molecules is contained in the DNA sequence. Some 100 of these tiny RNA genes have been found in the gut bacterium Escherichia coli, and some 200 were

37、 uncovered in DNA from mouse brain tissue. In the nematode and fruit fly, they seem to be involved in development; in E. coli, they may facilitate rapid responses to environmental change and could serve similar functions in mammals. Nature 391, 806 - 811 (19 February 1998)Potent and specific genetic

38、 interference by double-stranded RNA in Caenorhabditis elegans ANDREW FIRE*, SIQUN XU*, MARY K. MONTGOMERY*, STEVEN A. KOSTAS*, SAMUEL E. DRIVER & CRAIG C. MELLO * Carnegie Institution of Washington, Department of Embryology, 115 West University Parkway, Baltimore, Maryland 21210, USA Biology Gr

39、aduate Program, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, USA Program in Molecular Medicine, Department of Cell Biology, University of Massachusetts Cancer Center, Two Biotech Suite 213, 373 Plantation Street, Worcester, Massachusetts 01605, USA 1、非編碼RNA的主要部分是長(zhǎng)的

40、 200nt 100nt 長(zhǎng)鏈非編碼RNA(lncRNA)是一類(lèi)轉(zhuǎn)錄本長(zhǎng)度超過(guò)200nt的RNA分子，它們并不編碼蛋白，而是以RNA的形式在多種層面上（表觀遺傳調(diào)控、轉(zhuǎn)錄調(diào)控以及轉(zhuǎn)錄后調(diào)控等）調(diào)控基因的表達(dá)水平。 lncRNA起初被認(rèn)為是基因組轉(zhuǎn)錄的“噪音”，是RNA聚合酶II轉(zhuǎn)錄的副產(chǎn)物，不具有生物學(xué)功能。然而，近年來(lái)的研究表明，lncRNA參與了X染色體沉默，基因組印記以及染色質(zhì)修飾，轉(zhuǎn)錄激活，轉(zhuǎn)錄干擾，核內(nèi)運(yùn)輸?shù)榷喾N重要的調(diào)控過(guò)程，lncRNA的這些調(diào)控作用也開(kāi)始引起人們廣泛的關(guān)注。哺乳動(dòng)物基因組序列中約4%9%的序列產(chǎn)生的轉(zhuǎn)錄本是lncRNA（相應(yīng)的蛋白編碼RNA的比例是1%），雖然近

41、年來(lái)關(guān)于lncRNA的研究進(jìn)展迅猛，但是絕大部分的lncRNA的功能仍然是不清楚的。 許多l(xiāng)ncRNA都具有保守的二級(jí)結(jié)構(gòu)，剪切形式以及亞細(xì)胞定位，這種保守性和特異性表明它們是具有功能的。 有多少非編碼基因還沒(méi)被發(fā)現(xiàn)？ 幾年前，日本的遺傳研究所（RIKEN）在小鼠中獲得了約180,000個(gè)全長(zhǎng)的RNA轉(zhuǎn)錄本，其中編碼蛋白質(zhì)的轉(zhuǎn)錄本僅有約20,000個(gè)，其余約160,000個(gè)轉(zhuǎn)錄本全部歸屬于非編碼RNA。 transcriptional regulation For example, the ncRNA Evf-2 functions as a co-activator for the home

42、obox transcription factor Dlx2, which plays important roles in forebrain development and neurogenesis (Feng 2006; Panganiban 2002). Sonic hedgehog induces transcription of Evf-2 from an ultra-conserved element located between the Dlx5 and Dlx6 genes during forebrain development (Feng 2006). Evf-2 th

43、en recruits the Dlx2 transcription factor to the same ultra-conserved element whereby Dlx2 subsequently induces expression of Dlx5. The existence of other similar ultra- or highly conserved elements within the mammalian genome that are both transcribed and fulfil enhancer functions suggest Evf-2 may

44、 be illustrative of a generalised mechanism that tightly regulates important developmental genes with complex expression patterns during vertebrate growth (Pennacchio 2006; Visel 2008).Feng J, Bi C, Clark BS, Mady R, Shah P, Kohtz JD (June 2006). The Evf-2 noncoding RNA is transcribed from the Dlx-5

45、/6 ultraconserved region and functions as a Dlx-2 transcriptional coactivator. Genes & Development 20 (11): 147084. doi:10.1101/gad.1416106. PMC 1475760. PMID 16705037. The formation of RNA duplexes between complementary ncRNA and mRNA may mask key elements within the mRNA required to bind trans

46、-acting factors, potentially effecting any step in post-transcriptional gene expression including pre-mRNA processing and splicing, transport, translation, and degradation.The splicing of mRNA can induce its translation and functionally diversify the repertoire of proteins it encodes. The Zeb2 mRNA,

47、 which has a particularly long 5UTR, requires the retention of a 5UTR intron that contains an internal ribosome entry site for efficient translation (Beltran 2008). However, retention of the intron is dependent on the expression of an antisense transcript that complements the intronic 5 splice site

48、(Beltran 2008). Therefore, the ectopic expression of the antisense transcript represses splicing and induces translation of the Zeb2 mRNA during mesenchymal development.Post-transcriptional regulation Indeed it was recently shown that BC1 is associated with translational repression in dendrites to c

49、ontrol the efficiency of dopamine D2 receptor-mediated transmission in the striatum (Centonze 2007) and BC1 RNA-deleted mice exhibit behavioural changes with reduced exploration and increased anxiety (Lewejohann 2004).Centonze D, Rossi S, Napoli I, et al. (August 2007). The brain cytoplasmic RNA BC1

50、 regulates dopamine D2 receptor-mediated transmission in the striatum. The Journal of Neuroscience 27 (33): 888592. doi:10.1523/JNEUROSCI.0548-07.2007. PMID 17699670. Lewejohann L, Skryabin BV, Sachser N, et al. (September 2004). Role of a neuronal small non-messenger RNA: behavioural alterations in

51、 BC1 RNA-deleted mice. Behavioural Brain Research 154 (1): 27389. doi:10.1016/j.bbr.2004.02.015. PMID 15302134. translational regulation Epigenetic modifications, including histone and DNA methylation, histone acetylation and sumoylation, affect many aspects of chromosomal biology, primarily includi

52、ng regulation of large numbers of genes by remodeling broad chromatin domains. While it has been known for some time that RNA is an integral component of chromatin, it is only recently that we are beginning to appreciate the means by which RNA is involved in pathways of chromatin modification (Chen

53、2008; Rinn 2007; Sanchez-Elsner 2006)Chen X, Xu H, Yuan P, et al. (June 2008). Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133 (6): 110617. doi:10.1016/j.cell.2008.04.043. PMID 18555785. Rinn JL, Kertesz M, Wang JK, et al. (June 2007

54、). Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129 (7): 131123. doi:10.1016/j.cell.2007.05.022. PMC 2084369. PMID 17604720. Sanchez-Elsner T, Gou D, Kremmer E, Sauer F (February 2006). Noncoding RNAs of trithorax response elements recruit D

55、rosophila Ash1 to Ultrabithorax. Science 311 (5764): 111823. Bibcode:2006Sci.311.1118S. doi:10.1126/science.1117705. PMID 16497925. epigenetic regulation Imprinting Many emergent themes of ncRNA-directed chromatin modification were first apparent within the phenomenon of imprinting, whereby only one

56、 allele of a gene is expressed from either the maternal or the paternal chromosome. In general, imprinted genes are clustered together on chromosomes, suggesting the imprinting mechanism acts upon local chromosome domains rather than individual genes. These clusters are also often associated with lo

57、ng ncRNAs whose expression is correlated with the repression of the linked protein-coding gene on the same allele. Indeed, detailed analysis has revealed a crucial role for the ncRNAs Kcnqot1 and Igf2r/Air in directing imprinting (Braidotti 2004). Almost all the genes at the Kcnq1 loci are maternall

58、y inherited, except the paternally expressed antisense ncRNA Kcnqot1 (Mitsuya 1999).Braidotti G, Baubec T, Pauler F, et al. (2004). The Air noncoding RNA: an imprinted cis-silencing transcript. Cold Spring Harbor Symposia on Quantitative Biology 69: 5566. doi:10.1101/sqb.2004.69.55. PMID 16117633. M

59、itsuya K, Meguro M, Lee MP, et al. (July 1999). LIT1, an imprinted antisense RNA in the human KvLQT1 locus identified by screening for differentially expressed transcripts using monochromosomal hybrids. Human Molecular Genetics 8 (7): 120917. doi:10.1093/hmg/8.7.1209. PMID 10369866. Telomeres have b

60、een long considered transcriptionally inert DNA-protein complexes until it was recently shown that telomeric repeats may be transcribed as telomeric RNAs (TelRNAs) (Schoeftner 2008) or telomeric repeat-containing RNAs (Azzalin 2007). These ncRNAs are heterogeneous in length, transcribed from several sub-tel