Dark matter RNA illuminates the puzzle of genome-wide association studies

BMC Medicine

Philipp Kapranov¹  Yuri Vyatkin²  Georges St. Laurent¹ 

[1] St. Laurent Institute, 317 New Boston St, Suite 201, Woburn, MA 01801, USA;AcademGene Ltd., 6, Acad. Lavrentyev ave., Novosibirsk 630090, Russia

关键词: Very long intergenic non-coding RNA;    Long intergenic non-coding RNA;    Long Non-coding RNA;    LincRNA;    RNA scaffold;    lncRNA;    Intronic RNA;    vlincRNA;    Non-coding RNA;    Genome-wide association study;   

Others  :  840916
DOI  :  10.1186/1741-7015-12-97

 received in 2014-03-07, accepted in 2014-05-22,  发布年份 2014

【 摘 要 】

In the past decade, numerous studies have made connections between sequence variants in human genomes and predisposition to complex diseases. However, most of these variants lie outside of the charted regions of the human genome whose function we understand; that is, the sequences that encode proteins. Consequently, the general concept of a mechanism that translates these variants into predisposition to diseases has been lacking, potentially calling into question the validity of these studies. Here we make a connection between the growing class of apparently functional RNAs that do not encode proteins and whose function we do not yet understand (the so-called ‘dark matter’ RNAs) and the disease-associated variants. We review advances made in a different genomic mapping effort – unbiased profiling of all RNA transcribed from the human genome – and provide arguments that the disease-associated variants exert their effects via perturbation of regulatory properties of non-coding RNAs existing in mammalian cells.

【 授权许可】

   
2014 St. Laurent et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY, Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, Pericak-Vance MA: Complement factor H variant increases the risk of age-related macular degeneration. Science 2005, 308:419-421.
• [2]A Catalog of Published Genome-Wide Association Studies. http://www.genome.gov/gwastudies webcite
• [3]Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA: Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 2009, 106:9362-9367.
• [4]Barendse W: The effect of measurement error of phenotypes on genome wide association studies. BMC Genomics 2011, 12:232. BioMed Central Full Text
• [5]Cardon LR, Palmer LJ: Population stratification and spurious allelic association. Lancet 2003, 361:598-604.
• [6]Clayton DG, Walker NM, Smyth DJ, Pask R, Cooper JD, Maier LM, Smink LJ, Lam AC, Ovington NR, Stevens HE, Nutland S, Howson JM, Faham M, Moorhead M, Jones HB, Falkowski M, Hardenbol P, Willis TD, Todd JA: Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat Genet 2005, 37:1243-1246.
• [7]The Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007, 447:661-678.
• [8]Khurana E, Fu Y, Colonna V, Mu XJ, Kang HM, Lappalainen T, Sboner A, Lochovsky L, Chen J, Harmanci A, Das J, Abyzov A, Balasubramanian S, Beal K, Chakravarty D, Challis D, Chen Y, Clarke D, Clarke L, Cunningham F, Evani US, Flicek P, Fragoza R, Garrison E, Gibbs R, Gumus ZH, Herrero J, Kitabayashi N, Kong Y, Lage K, et al.: Integrative annotation of variants from 1092 humans: application to cancer genomics. Science 2013, 342:1235587.
• [9]Kapranov P, Cawley SE, Drenkow J, Bekiranov S, Strausberg RL, Fodor SP, Gingeras TR: Large-scale transcriptional activity in chromosomes 21 and 22. Science 2002, 296:916-919.
• [10]Kapranov P, St Laurent G: Dark Matter RNA: Existence, Function, and Controversy. Front Genet 2012, 3:60.
• [11]Clark MB, Choudhary A, Smith MA, Taft RJ, Mattick JS: The dark matter rises: the expanding world of regulatory RNAs. Essays Biochem 2013, 54:1-16.
• [12]Mudge JM, Frankish A, Harrow J: Functional transcriptomics in the post-ENCODE era. Genome Res 2013, 23:1961-1973.
• [13]Clark MB, Amaral PP, Schlesinger FJ, Dinger ME, Taft RJ, Rinn JL, Ponting CP, Stadler PF, Morris KV, Morillon A, Rozowsky JS, Gerstein MB, Wahlestedt C, Hayashizaki Y, Carninci P, Gingeras TR, Mattick JS: The reality of pervasive transcription. PLoS Biol 2011, 9:e1000625. discussion e1001102
• [14]Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi T, Lenhard B, Wells C, Kodzius R, Shimokawa K, Bajic VB, Brenner SE, Batalov S, Forrest AR, Zavolan M, Davis MJ, Wilming LG, Aidinis V, Allen JE, Ambesi-Impiombato A, Apweiler R, Aturaliya RN, Bailey TL, Bansal M, Baxter L, Beisel KW, Bersano T, Bono H, et al.: The transcriptional landscape of the mammalian genome. Science 2005, 309:1559-1563.
• [15]Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE, Kuehn MS, Taylor CM, Neph S, Koch CM, Asthana S, Malhotra A, Adzhubei I, Greenbaum JA, Andrews RM, Flicek P, Boyle PJ, Cao H, Carter NP, Clelland GK, Davis S, Day N, Dhami P, Dillon SC, Dorschner MO, Fiegler H, et al.: Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007, 447:799-816.
• [16]Okazaki Y, Furuno M, Kasukawa T, Adachi J, Bono H, Kondo S, Nikaido I, Osato N, Saito R, Suzuki H, Yamanaka I, Kiyosawa H, Yagi K, Tomaru Y, Hasegawa Y, Nogami A, Schonbach C, Gojobori T, Baldarelli R, Hill DP, Bult C, Hume DA, Quackenbush J, Schriml LM, Kanapin A, Matsuda H, Batalov S, Beisel KW, Blake JA, Bradt D, et al.: Analysis of the mouse transcriptome based on functional annotation of 60,770 full-length cDNAs. Nature 2002, 420:563-573.
• [17]Bertone P, Stolc V, Royce TE, Rozowsky JS, Urban AE, Zhu X, Rinn JL, Tongprasit W, Samanta M, Weissman S, Gerstein M, Snyder M: Global identification of human transcribed sequences with genome tiling arrays. Science 2004, 306:2242-2246.
• [18]Cheng J, Kapranov P, Drenkow J, Dike S, Brubaker S, Patel S, Long J, Stern D, Tammana H, Helt G, Sementchenko V, Piccolboni A, Bekiranov S, Bailey DK, Ganesh M, Ghosh S, Bell I, Gerhard DS, Gingeras TR: Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution. Science 2005, 308:1149-1154.
• [19]Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, Stadler PF, Hertel J, Hackermuller J, Hofacker IL, Bell I, Cheung E, Drenkow J, Dumais E, Patel S, Helt G, Ganesh M, Ghosh S, Piccolboni A, Sementchenko V, Tammana H, Gingeras TR: RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science 2007, 316:1484-1488.
• [20]Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Roder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K, Bell I, Chakrabortty S, Chen X, Chrast J, Curado J, et al.: Landscape of transcription in human cells. Nature 2012, 489:101-108.
• [21]Kapranov P, St Laurent G, Raz T, Ozsolak F, Reynolds CP, Sorensen PH, Reaman G, Milos P, Arceci RJ, Thompson JF, Triche TJ: The majority of total nuclear-encoded non-ribosomal RNA in a human cell is 'dark matter' un-annotated RNA. BMC Biol 2010, 8:149. BioMed Central Full Text
• [22]Denoeud F, Kapranov P, Ucla C, Frankish A, Castelo R, Drenkow J, Lagarde J, Alioto T, Manzano C, Chrast J, Dike S, Wyss C, Henrichsen CN, Holroyd N, Dickson MC, Taylor R, Hance Z, Foissac S, Myers RM, Rogers J, Hubbard T, Harrow J, Guigo R, Gingeras TR, Antonarakis SE, Reymond A: Prominent use of distal 5' transcription start sites and discovery of a large number of additional exons in ENCODE regions. Genome Res 2007, 17:746-759.
• [23]Mercer TR, Gerhardt DJ, Dinger ME, Crawford J, Trapnell C, Jeddeloh JA, Mattick JS, Rinn JL: Targeted RNA sequencing reveals the deep complexity of the human transcriptome. Nat Biotechnol 2012, 30:99-104.
• [24]Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A, Regev A, Lander ES, Rinn JL: Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A 2009, 106:11667-11672.
• [25]Kim TK, Hemberg M, Gray JM, Costa AM, Bear DM, Wu J, Harmin DA, Laptewicz M, Barbara-Haley K, Kuersten S, Markenscoff-Papadimitriou E, Kuhl D, Bito H, Worley PF, Kreiman G, Greenberg ME: Widespread transcription at neuronal activity-regulated enhancers. Nature 2010, 465:182-187.
• [26]Wahlestedt C: Targeting long non-coding RNA to therapeutically upregulate gene expression. Nat Rev Drug Discov 2013, 12:433-446.
• [27]Kapranov P, Willingham AT, Gingeras TR: Genome-wide transcription and the implications for genomic organization. Nat Rev Genet 2007, 8:413-423.
• [28]St Laurent G 3rd, Shtokalo D, Tackett M, Yang Z, Eremina T, Wahlestedt C, Inchima SU, Seilheimer B, McCaffrey TA, Kapranov P: Intronic RNAs constitute the major fraction of the non-coding RNA in mammalian cells. BMC Genomics 2012, 13:504. BioMed Central Full Text
• [29]Gardner EJ, Nizami ZF, Talbot CC Jr, Gall JG: Stable intronic sequence RNA (sisRNA), a new class of noncoding RNA from the oocyte nucleus of Xenopus tropicalis. Genes Dev 2012, 26:2550-2559.
• [30]Mattick JS: Introns: evolution and function. Curr Opin Genet Dev 1994, 4:823-831.
• [31]St Laurent G, Shtokalo D, Dong B, Tackett M, Fan X, Lazorthes S, Nicolas E, Sang N, Triche T, McCaffrey T, Xiao W, Kapranov P: VlincRNAs controlled by retroviral elements are a hallmark of pluripotency and cancer. Genome Biology 2013, 14:R73. BioMed Central Full Text
• [32]Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N, Ward LD, Epstein CB, Zhang X, Wang L, Issner R, Coyne M, Ku M, Durham T, Kellis M, Bernstein BE: Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 2011, 473:43-49.
• [33]Nissan A, Stojadinovic A, Mitrani-Rosenbaum S, Halle D, Grinbaum R, Roistacher M, Bochem A, Dayanc BE, Ritter G, Gomceli I, Bostanci EB, Akoglu M, Chen YT, Old LJ, Gure AO: Colon cancer associated transcript-1: a novel RNA expressed in malignant and pre-malignant human tissues. Int J Cancer 2012, 130:1598-1606.
• [34]Ling H, Spizzo R, Atlasi Y, Nicoloso M, Shimizu M, Redis RS, Nishida N, Gafa R, Song J, Guo Z, Ivan C, Barbarotto E, De Vries I, Zhang X, Ferracin M, Churchman M, van Galen JF, Beverloo BH, Shariati M, Haderk F, Estecio MR, Garcia-Manero G, Patijn GA, Gotley DC, Bhardwaj V, Shureiqi I, Sen S, Multani AS, Welsh J, Yamamoto K, et al.: CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res 2013, 23:1446-1461.
• [35]Pasmant E, Sabbagh A, Vidaud M, Bieche I: ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS. FASEB J 2011, 25:444-448.
• [36]Holdt LM, Hoffmann S, Sass K, Langenberger D, Scholz M, Krohn K, Finstermeier K, Stahringer A, Wilfert W, Beutner F, Gielen S, Schuler G, Gabel G, Bergert H, Bechmann I, Stadler PF, Thiery J, Teupser D: Alu elements in ANRIL non-coding RNA at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks. PLoS Genet 2013, 9:e1003588.
• [37]Gong C, Tang Y, Maquat LE: mRNA-mRNA duplexes that autoelicit Staufen1-mediated mRNA decay. Nat Struct Mol Biol 2013, 20:1214-1220.
• [38]Wang J, Gong C, Maquat LE: Control of myogenesis by rodent SINE-containing lncRNAs. Genes Dev 2013, 27:793-804.
• [39]St Laurent G, Savva YA, Kapranov P: Dark matter RNA: an intelligent scaffold for the dynamic regulation of the nuclear information landscape. Front Genet 2012, 3:57.
• [40]Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S, Chang HY: Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 2010, 464:1071-1076.
• [41]van Dijk M, Thulluru HK, Mulders J, Michel OJ, Poutsma A, Windhorst S, Kleiverda G, Sie D, Lachmeijer AM, Oudejans CB: HELLP babies link a novel lincRNA to the trophoblast cell cycle. J Clin Invest 2012, 122:4003-4011.
• [42]Kerin T, Ramanathan A, Rivas K, Grepo N, Coetzee GA, Campbell DB: A noncoding RNA antisense to moesin at 5p14.1 in autism. Sci Transl Med 2012, 4:128ra140.
• [43]Askarian-Amiri ME, Crawford J, French JD, Smart CE, Smith MA, Clark MB, Ru K, Mercer TR, Thompson ER, Lakhani SR, Vargas AC, Campbell IG, Brown MA, Dinger ME, Mattick JS: SNORD-host RNA Zfas1 is a regulator of mammary development and a potential marker for breast cancer. RNA 2011, 17:878-891.
• [44]Khaitan D, Dinger ME, Mazar J, Crawford J, Smith MA, Mattick JS, Perera RJ: The melanoma-upregulated long noncoding RNA SPRY4-IT1 modulates apoptosis and invasion. Cancer Res 2011, 71:3852-3862.
• [45]Abdelmohsen K, Panda A, Kang MJ, Xu J, Selimyan R, Yoon JH, Martindale JL, De S, Wood WH 3rd, Becker KG, Gorospe M: Senescence-associated lncRNAs: senescence-associated long noncoding RNAs. Aging Cell 2013, 12:890-900.
• [46]Vergara IA, Erho N, Triche TJ, Ghadessi M, Crisan A, Sierocinski T, Black PC, Buerki C, Davicioni E: Genomic "Dark Matter" in Prostate Cancer: Exploring the Clinical Utility of ncRNA as Biomarkers. Front Genet 2012, 3:23.
• [47]Reis EM, Verjovski-Almeida S: Perspectives of Long Non-Coding RNAs in Cancer Diagnostics. Front Genet 2012, 3:32.