Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Analysis of Trans-splicing Transcripts in Embryonic Stem Cell

배아줄기세포에서 트랜스 스플라이싱 전사체의 분석

  • Ha, Hong-Seok (Department of Biological Sciences, College of Natural Sciences, Pusan National University) ;
  • Huh, Jae-Won (National Primate Research Center, KRIBB) ;
  • Kim, Dae-Soo (Korean BioInformation Center, KRIBB) ;
  • Park, Sang-Je (Department of Biological Sciences, College of Natural Sciences, Pusan National University) ;
  • Bae, Jin-Han (Department of Biological Sciences, College of Natural Sciences, Pusan National University) ;
  • Ahn, Kung (Department of Biological Sciences, College of Natural Sciences, Pusan National University) ;
  • Yun, Se-Eun (Department of Biological Sciences, College of Natural Sciences, Pusan National University) ;
  • Kim, Heui-Soo (Department of Biological Sciences, College of Natural Sciences, Pusan National University)
  • 하홍석 (부산대학교 자연과학대학 생명과학과) ;
  • 허재원 (한국생명공학연구원 국가영장류센터) ;
  • 김대수 (한국생명공학연구원 국가생물자원정보관리센터) ;
  • 박상제 (부산대학교 자연과학대학 생명과학과) ;
  • 배진한 (부산대학교 자연과학대학 생명과학과) ;
  • 안궁 (부산대학교 자연과학대학 생명과학과) ;
  • 윤세은 (부산대학교 자연과학대학 생명과학과) ;
  • 김희수 (부산대학교 자연과학대학 생명과학과)
  • Published : 2009.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Genetic mutations by gene fusion result from chromosomal rearrangement, trans-splicing, and intergenic splicing. Trans-splicing is a phenomenon in which two pre-mRNAs grow together into one. We analyzed the trans-splicing products in embryonic stem cells. By using bioinformatic tools, 70 trans-splicing transcripts were identified. They are classified into 6 types according to fusion pattern: 5'UTR-5'UTR, 5'UTR-3'UTR, 3'UTR-3'UTR, 5'UTR-CDS, 3'UTR-CDS, CDS-CDS. The fusion products are more abundant in CDS regions than in UTR regions, which contain multiple intron numbers. Chromosome analysis showing gene fusion via trans-splicing indicated that chromosomes 17 and 19 were activated. These data are of great use for further studies in relation to fusion genes and human diseases.

유전자의 융합으로 인한 돌연변이는 염색체 재배열, 트랜스 스플라이싱, 유전자간 스플라이싱으로 인하여 야기된다고 알려져 있다. 우리는 두 개의 서로 다른 유전자의 pre-mRNA의 융합으로 인하여 만들어지는 트랜스 스플라이싱의 전사 산물에 관심을 가져, 인간의 태아 줄기 세포에서 이러한 돌연변이 양상을 분석하였다. 배아줄기세포의 mRNA에서 트랜스 스플라이싱 전사체 70개를 탐지해 내고, 이들의 융합되는 패턴에 따라 5'UTR-5'UTR, 5'UTR-3'UTR, 3'UTR-3'UTR, 5'UTR- CDS, 3'UTR-CDS, CDS-CDS의 6개의 유형으로 분류하여 분석하였다. 두 유전자의 융합되는 영역은 UTR영역보다 CDS에서 풍부하였는데, 이러한 이유는 많은 인트론 수로 인해 야기되는 것으로 추정된다. 융합되는 유전자의 염색체상의 위치분석 결과, 17번과 19번 염색체가 융합유전자의 활성화를 나타내었다. 이러한 연구결과는 향후 융합유전자와 인간의 질병 연구에 크게 기여할 것으로 사료된다.

Keywords

References

  1. Bernard, O., N. Lecointe, P. Jonveaux, M. Souyri, M. Mauchauffe, R. Berger, C. J. Larsen, and D. Mathieu-Mahul. 1991. Two site-specific deletions and t(1;14) translocation restricted to human T-cell acute leukemias disrupt the 5' part of the tal-1 gene. Oncogene 6, 1477-1488
  2. Bonen, L. 1993. Trans-splicing of pre-mRNA in plants, animals, and protists. FASEB J. 7, 40-46
  3. Breen, M. A. and S. J. Ashcroft. A truncated isoform of Ca2+/ calmodulin-dependent protein kinase II expressed in human islets of Langerhans may result from trans-splicing. FEBS Lett. 1997 409, 375-379 https://doi.org/10.1016/S0014-5793(97)00555-3
  4. Bruzik, J. P. and T. Maniatis. 1992. Spliced leader RNAs from lower eukaryotes are trans-spliced in mammalian cells. Nature 360, 692-695 https://doi.org/10.1038/360692a0
  5. Caudevilla, C., D. Serra, A. Miliar, C. Codony, G. Asins, M. Bach, and F. G. Hegardt. 1998. Natural trans-splicing in carnitine octanoyltransferase pre-mRNAs in rat liver. Proc. Natl. Acad. Sci. USA 95, 12185-12190 https://doi.org/10.1073/pnas.95.21.12185
  6. Cleary, M. L., S. D. Smith, and J. Sklar. 1986. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47, 19-28 https://doi.org/10.1016/0092-8674(86)90362-4
  7. Hockenbery, D., G. Nunez, C. Milliman, R. D. Schreiber, and S. J. Korsmeyer. 1990. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348, 334-346 https://doi.org/10.1038/348334a0
  8. Hong, X., D. G. Scofield, and M. Lynch. 2006. Intron size, abundance, and distribution within untranslated regions of genes. Mol. Biol. Evol. 23, 2392-2404 https://doi.org/10.1093/molbev/msl111
  9. Janz, S., M. Potter, and C. S. Rabkin. 2003. Lymphoma- and leukemia-associated chromosomal translocations in healthy individuals. Genes Chromosomes Cancer 36, 211-223 https://doi.org/10.1002/gcc.10178
  10. Kourlas, P. J., M. P. Strout, B. Becknell, M. L. Veronese, C. M. Croce, K. S. Theil, R. Krahe, T. Ruutu, S. Knuutila, C. D. Bloomfield, and M. A. Caligiuri. 2000. Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: evidence for its fusion with MLL in acute myeloid leukemia. Proc. Natl. Acad. Sci. USA 97, 2145-2150
  11. Li, H., J. Wang, G. Mor, and J. Sklar. 2008. A neoplastic gene fusion mimics trans-splicing of RNAs in normal hu-man cells. Science 321, 1357-1361 https://doi.org/10.1126/science.1156725
  12. Lidie, K. B. and F. M. van Dolah. 2007. Spliced leader RNA-mediated trans-splicing in a dinoflagellate, Karenia brevis. J. Eukaryot Microbiol. 54, 427-435 https://doi.org/10.1111/j.1550-7408.2007.00282.x
  13. Mitelman, F., B. Johansson, and F. Mertens. 2007. The impact of translocations and gene fusions on cancer causation. Nat. Rev. Cancer 7, 233-245 https://doi.org/10.1038/nrc2091
  14. Mignone, F., C. Gissi, S. Liuni, and G. Pesole. 2002. Untranslated regions of mRNAs. Genome Biol. 3, e0004.1-0004.9
  15. Mikkelsen, T. and W. K. Cavenee. 1990. Suppressors of the malignant phenotype. Cell Growth Differ. 1, 201-207
  16. Nishikura, K., A. ar-Rushdi, J. Erikson, R. Watt, G. Rovera, and C. M. Croce. 1983. Differential expression of the normal and of the translocated human c-myc oncogenes in B cells. Proc. Natl. Acad. Sci. USA 80, 4822-4826 https://doi.org/10.1073/pnas.80.15.4822
  17. Pardanani, A., R. P. Ketterling, S. R. Brockman, H. C. Flynn, S. F. Paternoster, B. M. Shearer, T. L. Reeder, C. Y. Li, N. C. Cross, J. Cools, D. G. Gilliland, G. W. Dewald, and A. Tefferi. 2003. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood 102, 3093-3096 https://doi.org/10.1182/blood-2003-05-1627
  18. Pierotti, M. A., M. Santoro, R. B. Jenkins, G. Sozzi, I. Bongarzone, M. Grieco, N. Monzini, M. Miozzo, M. A. Herrmann, A. Fusco, I. D. Hay, G. D. Porta, and G. Vecchio. 1992. Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC. Proc. Natl. Acad. Sci. USA 89, 1616-1620 https://doi.org/10.1073/pnas.89.5.1616
  19. Shimizu, A. and T. Honjo. 1993. Synthesis and regulation of trans-mRNA encoding the immunoglobulin epsilon heavy chain. FASEB. J. 7, 149-154
  20. Shtivelman, E., B. Lifshitz, R. P. Gale, and E. Canaani. 1985. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature 315, 550-554 https://doi.org/10.1038/315550a0
  21. Sullivan, P. M., P. Petrusz, C. Szpirer, and D. R. Joseph. 1991. Alternative processing of androgen-binding protein RNA transcripts in fetal rat liver. Identification of a transcript formed by trans splicing. J. Biol. Chem. 266, 143-154
  22. Testa, J. R., M. Park, D. G. Blair, A. Kalbakji, K. Arden, and G. F. Vande Woude. 1990. Analysis by pulsed field gel electrophoresis reveals complex rearrangements in two MET alleles in a chemically-treated human cell line, MNNG-HOS. Oncogene 5, 1565-1571
  23. Tomlins, S. A., D. R. Rhodes, S. Perner, S. M. Dhanasekaran, R. Mehra, X. W. Sun, S. Varambally, X. Cao, J. Tchinda, R. Kuefer, C. Lee , J. E. Montie, R. B. Shah, K. J. Pienta, M. A. Rubin, and A. M. Chinnaiyan. 2005. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644-648 https://doi.org/10.1126/science.1117679
  24. Vellard, M., A. Sureau, J. Soret, C. Martinerie, and B. Perbal. 1992. A potential splicing factor is encoded by the opposite strand of the trans-spliced c-myb exon. Proc. Natl. Acad. Sci. USA 89, 2511-2515 https://doi.org/10.1073/pnas.89.7.2511