#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Discovery of CTCF-Sensitive Cis-Spliced Fusion RNAs between Adjacent Genes in Human Prostate Cells


Genes are considered the units of hereditary information; thus, neither genes nor their encoded products are expected to mingle with each other unless in some disease situations. However, the genes are not alone in the genome. Genes have neighbors, some close, some far. With RNA-seq, many fusion RNAs involving neighboring genes are being identified. However, little is done to validate and characterize the fusion RNAs. Using one prostate cell line and a discovery pipeline for cis-splicing between adjacent genes (cis-SAGe), we found 16 new such events. We then developed a set of rules based on the characteristics of these fusion RNAs, and applied them to 20 random neighboring gene pairs. Four turned out to be true. The majority of the fusions are found in cancer cells, as well as in non-cancer cells. These results suggest that the genes are “leaky”, and the fusions are not limited to cancer cells.


Vyšlo v časopise: Discovery of CTCF-Sensitive Cis-Spliced Fusion RNAs between Adjacent Genes in Human Prostate Cells. PLoS Genet 11(2): e32767. doi:10.1371/journal.pgen.1005001
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005001

Souhrn

Genes are considered the units of hereditary information; thus, neither genes nor their encoded products are expected to mingle with each other unless in some disease situations. However, the genes are not alone in the genome. Genes have neighbors, some close, some far. With RNA-seq, many fusion RNAs involving neighboring genes are being identified. However, little is done to validate and characterize the fusion RNAs. Using one prostate cell line and a discovery pipeline for cis-splicing between adjacent genes (cis-SAGe), we found 16 new such events. We then developed a set of rules based on the characteristics of these fusion RNAs, and applied them to 20 random neighboring gene pairs. Four turned out to be true. The majority of the fusions are found in cancer cells, as well as in non-cancer cells. These results suggest that the genes are “leaky”, and the fusions are not limited to cancer cells.


Zdroje

1. Nigro JM, Cho KR, Fearon ER, Kern SE, Ruppert JM, et al. (1991) Scrambled exons. Cell 64: 607–613. 1991322

2. Li H, Wang J, Mor G, Sklar J (2008) A Neoplastic Gene Fusion Mimics Trans-Splicing of RNAs in Normal Human Cells. Science 321: 1357–1361. doi: 10.1126/science.1156725 18772439

3. Zaphiropoulos PG (2012) Genetic variations and alternative splicing: the Glioma associated oncogene 1, GLI1. Frontiers in genetics 3: 119. doi: 10.3389/fgene.2012.00119 22833753

4. Velusamy T, Palanisamy N, Kalyana-Sundaram S, Sahasrabuddhe AA, Maher CA, et al. (2013) Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America 110: 3035–3040. doi: 10.1073/pnas.1214326110 23382248

5. Maher CA, Kumar-Sinha C, Cao X, Kalyana-Sundaram S, Han B, et al. (2009) Transcriptome sequencing to detect gene fusions in cancer. Nature 458: 97–101. doi: 10.1038/nature07638 19136943

6. Rickman DS, Pflueger D, Moss B, VanDoren VE, Chen CX, et al. (2009) SLC45A3-ELK4 is a novel and frequent erythroblast transformation-specific fusion transcript in prostate cancer. Cancer Res 69: 2734–2738. doi: 10.1158/0008-5472.CAN-08-4926 19293179

7. Zhang Y, Gong M, Yuan H, Park HG, Frierson HF, et al. (2012) Chimeric Transcript Generated by cis-Splicing of Adjacent Genes Regulates Prostate Cancer Cell Proliferation. Cancer Discovery 2: 598–607. doi: 10.1158/2159-8290.CD-12-0042 22719019

8. Kumar-Sinha C, Kalyana-Sundaram S, Chinnaiyan AM (2012) SLC45A3-ELK4 Chimera in Prostate Cancer: Spotlight on cis-Splicing. Cancer Discovery 2: 582–585. doi: 10.1158/2159-8290.CD-12-0212 22787087

9. Akiva P, Toporik A, Edelheit S, Peretz Y, Diber A, et al. (2006) Transcription-mediated gene fusion in the human genome. Genome Res 16: 30–36. 16344562

10. Nacu S, Yuan W, Kan Z, Bhatt D, Rivers CS, et al. Deep RNA sequencing analysis of readthrough gene fusions in human prostate adenocarcinoma and reference samples. BMC Med Genomics 4: 11. doi: 10.1186/1755-8794-4-11 21261984

11. Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, et al. (2011) The genomic complexity of primary human prostate cancer. Nature 470: 214–220. doi: 10.1038/nature09744 21307934

12. Beillard E, Ong SC, Giannakakis A, Guccione E, Vardy LA, et al. miR-Sens—a retroviral dual-luciferase reporter to detect microRNA activity in primary cells. RNA 18: 1091–1100. doi: 10.1261/rna.031831.111 22417692

13. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, et al. (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310: 644–648. 16254181

14. Jia W, Qiu K, He M, Song P, Zhou Q, et al. SOAPfuse: an algorithm for identifying fusion transcripts from paired-end RNA-Seq data. Genome Biol 14: R12. doi: 10.1186/gb-2013-14-2-r12 23409703

15. Ren S, Peng Z, Mao JH, Yu Y, Yin C, et al. RNA-seq analysis of prostate cancer in the Chinese population identifies recurrent gene fusions, cancer-associated long noncoding RNAs and aberrant alternative splicings. Cell Res 22: 806–821. doi: 10.1038/cr.2012.30 22349460

16. Fagerberg L, Hallstrom BM, Oksvold P, Kampf C, Djureinovic D, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics 13: 397–406. doi: 10.1074/mcp.M113.035600 24309898

17. Ong CT, Corces VG (2009) Insulators as mediators of intra- and inter-chromosomal interactions: a common evolutionary theme. Journal of biology 8: 73. doi: 10.1186/jbiol165 19725934

18. Scott SL, Earle JD, Gumerlock PH (2003) Functional p53 increases prostate cancer cell survival after exposure to fractionated doses of ionizing radiation. Cancer Res 63: 7190–7196. 14612513

19. Koralewski TE, Krutovsky KV Evolution of exon-intron structure and alternative splicing. PLoS One 6: e18055. doi: 10.1371/journal.pone.0018055 21464961

20. de la Mata M, Alonso CR, Kadener S, Fededa JP, Blaustein M, et al. (2003) A slow RNA polymerase II affects alternative splicing in vivo. Mol Cell 12: 525–532. 14536091

21. Sharov AA, Ko MS (2009) Exhaustive search for over-represented DNA sequence motifs with CisFinder. DNA Res 16: 261–273. doi: 10.1093/dnares/dsp014 19740934

22. Burset M, Seledtsov IA, Solovyev VV (2000) Analysis of canonical and non-canonical splice sites in mammalian genomes. Nucleic Acids Res 28: 4364–4375. 11058137

23. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29: 15–21. doi: 10.1093/bioinformatics/bts635 23104886

24. Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, et al. Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol 29: 742–749. doi: 10.1038/nbt.1914 21804560

25. Fagerberg L, Hallstrom BM, Oksvold P, Kampf C, Djureinovic D, et al. (2014) Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Molecular & cellular proteomics: MCP 13: 397–406. doi: 10.1038/ncomms7071 25608249

26. Wang K, Ubriaco G, Sutherland LC (2007) RBM6-RBM5 transcription-induced chimeras are differentially expressed in tumours. BMC Genomics 8: 348. 17908320

27. Kannan K, Wang L, Wang J, Ittmann MM, Li W, et al. Recurrent chimeric RNAs enriched in human prostate cancer identified by deep sequencing. Proc Natl Acad Sci U S A 108: 9172–9177. doi: 10.1073/pnas.1100489108 21571633

28. Houseley J, Tollervey D Apparent non-canonical trans-splicing is generated by reverse transcriptase in vitro. PLoS One 5: e12271. doi: 10.1371/journal.pone.0012271 20805885

29. Phillips JE, Corces VG (2009) CTCF: master weaver of the genome. Cell 137: 1194–1211. doi: 10.1016/j.cell.2009.06.001 19563753

30. Burgess-Beusse B, Farrell C, Gaszner M, Litt M, Mutskov V, et al. (2002) The insulation of genes from external enhancers and silencing chromatin. Proc Natl Acad Sci U S A 99 Suppl 4: 16433–16437. 12154228

31. Handoko L, Xu H, Li G, Ngan CY, Chew E, et al. (2011) CTCF-mediated functional chromatin interactome in pluripotent cells. Nature genetics 43: 630–638. doi: 10.1038/ng.857 21685913

32. Ong CT, Corces VG (2014) CTCF: an architectural protein bridging genome topology and function. Nature reviews Genetics 15: 234–246. doi: 10.1038/nrg3663 24614316

33. Machida YJ, Chen Y, Machida Y, Malhotra A, Sarkar S, et al. (2006) Targeted comparative RNA interference analysis reveals differential requirement of genes essential for cell proliferation. Mol Biol Cell 17: 4837–4845. 16957053

34. Krzywinski M, Schein J, Birol I, Connors J, Gascoyne R, et al. (2009) Circos: an information aesthetic for comparative genomics. Genome Res 19: 1639–1645. doi: 10.1101/gr.092759.109 19541911

35. Saeed AI, Sharov V, White J, Li J, Liang W, et al. (2003) TM4: a free, open-source system for microarray data management and analysis. Biotechniques 34: 374–378. 12613259

36. Nguyen CD, Carlin JB, Lee KJ Diagnosing problems with imputation models using the Kolmogorov-Smirnov test: a simulation study. BMC Med Res Methodol 13: 144. doi: 10.1186/1471-2288-13-144 24252653

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2015 Číslo 2
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#