Los ARNs no codificantes largos y su vinculación con las patologías testiculares

Contenido principal del artículo

María F. Trovero
Adriana Geisinger

Resumen

Si bien la porción del genoma destinada a la síntesis de proteínas es muy pequeña, actualmente se sabe que casi todo el genoma se expresa bajo forma de ARNs no codificantes. Entre dichos ARNs se encuentran los ARNs no codificantes largos (lncRNAs). Aunque los lncRNAs han sido muy poco estudiados, recientemente han comenzado a centrar la atención de los investigadores, al descubrirse que los mismos pueden desempeñar diversas funciones en la regulación de la expresión génica. Además, su vinculación con patologías ha comenzado a ser puesta de manifiesto. Curiosamente, la cantidad de lncRNAs presentes en el testículo es abrumadoramente mayor que en cualquier otro órgano o tejido estudiado. Los perfiles de expresión de estos lncRNAs varían significativamente a lo largo de la espermatogénesis, y algunas evidencias sugieren que al menos algunos de ellos podrían participar en el proceso de formación de células germinales masculinas. No obstante, el conocimiento sobre el tema es aún muy escaso. En este trabajo revisamos la información disponible sobre la expresión de lncRNAs en el testículo y sus posibles funciones. Asimismo, analizamos algunos ejemplos que ilustran la participación de lncRNAs en el desarrollo de patologías como la infertilidad y el cáncer testicular.

Detalles del artículo

Cómo citar
Trovero, M. F., & Geisinger, A. (2019). Los ARNs no codificantes largos y su vinculación con las patologías testiculares. Anales De La Facultad De Medicina, Universidad De La República, Uruguay, 6(1), 10-27. https://doi.org/10.25184/anfamed2019v6n1a8
Sección
Revisión invitada
Biografía del autor/a

María F. Trovero, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE)

Departamento de Biología Molecular, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE)

Adriana Geisinger, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE) Facultad de Ciencias, Universidad de la República

Departamento de Biología Molecular, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Sección Bioquímica/Biología Molecular, Facultad de Ciencias

Citas

1. Mattick JS. The central role of RNA in human development and cognition. FEBS Lett. 2011;585(11):1600-16.

2. Luk AC, Chan WY, Rennert OM, Lee TL. Long noncoding RNAs in spermatogenesis: insights from recent high-throughput transcriptome studies. Reproduction. 2014;147(5):131-41.

3. Ghildiyal M, Zamore PD. Small silencing RNAs: an expanding universe. Nat Rev Genet. 2009;10(2):94-108.

4. Atkinson SR, Marguerat S, Bähler J. Exploring long non-coding RNAs through sequencing. Semin Cell Dev Biol. 2012;23(2):200-205.

5. Li LJ, Leng RX, Fan YG, Pan HF, Ye DQ. Translation of noncoding RNAs: Focus on lncRNAs, pri-miRNAs, and circRNAs. Exp Cell Res. 2017;361(1):1-8.

6. Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, et al. The landscape of long noncoding RNAs in the human transcriptome. Nat Genet. 2015;47(3):199-208.

7. Dinger ME, Amaral PP, Mercer TR, Pang KC, Bruce SJ, Gardiner BB, et al. Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation. Genome Res. 2008;18(9):1433-45.

8. Mercer TR, Dinger ME, Sunkin SM, Mehler MF, Mattick JS. Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci USA. 2008;105(2):716-21.

9. Pauli A, Valen E, Lin MF, Garber M, Vastenhouw NL, Levin JZ, et al. Systematic identification of long noncoding RNAs expressed during zebrafish embryogenesis. Genome Res. 2012;22(3):577-91.

10. Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 2009;458(7235):223-7.

11. Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 2011;25(18):1915-27.

12. De Hoon M, Shin JW, Carninci P. Paradigm shifts in genomics through the Fantom projects. Mamm Genome. 2015;26(9-10):391-402.

13. Lü M, Tian H, Cao YX, He X, Chen L, Song X, et al. Downregulation of miR-320a/383-sponge-like long noncoding RNA NLC1-C (narcolepsy candidate-region 1 genes) is associated with male infertility and promotes testicular embryonal carcinoma cell proliferation. Cell Death Dis. 2015;6:e1960.

14. Hong SH, Kwon JT, Kim J, Jeong J, Kim J, Lee S, et al. Profiling of testis-specific long noncoding RNAs in mice. BMC Genomics. 2018;19:539.

15. Sanchez Calle A, Kawamura Y, Yamamoto Y, Takeshita F, Ochiya T. Emerging roles of long non-coding RNA in cancer. Cancer Sci. 2018;109(7):2093-2100.

16. Kamikawa Y, Donohoe ME. The dynamics of X-chromosome inactivation in mouse development. Mol Reprod Dev. 2014;81(2):141-7.

17. Pontier DB, Gribnau J. Xist regulation and function eXplored. Hum Genet. 2011;130(2):223-36.

18. Froberg JE, Yang L, Lee JT. Guided by RNAs: X-inactivation as a model for lncRNA function. J Mol Biol. 2013;425(19): 3698-706.

19. Wei JW, Huang K, Yang C, Kang CS. Non-coding RNAs as regulators in epigenetics. Oncol Rep. 2017;37(1):3-9.

20. Cai X, Cullen BR. The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA. 2007;13(3):313-6.

21. Bhartiya D, Kapoor S, Jalali S, Sati S, Kaushik K, Sachidanandan C, et al. Conceptual approaches for lncRNA drug discovery and future strategies. Expert Opin Drug Discov. 2012;7(6):503-13.

22. Calin GA, Liu CG, Ferracin, M, Hyslop T, Spizzo R, Sevignani C, et al. Ultranconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell. 2007;12(3):215-29.

23. Azzi S, Abi Habib W, Netchine I. Beckwith-Wiedemann and Russell-Silver syndromes: from new molecular insights to the comprehension of imprinting regulation. Curr Opin Endocrinol Diabetes Obes. 2017;21(1):30-8.

24. Raveh E, Matouk IJ, Gilon M, Hochberg A. The H19 long non-coding RNA in cancer initiation, progression and metastasis - A proposed unifying theory. Mol Cancer. 2015;14:184.

25. Dong X, He X, Guan A, Huang W, Jia H, Huang Y, et al. Long non-coding RNA Hotair promotes gastric cancer progression via miR-217-GPC5 axis. Life Sci. 2019;217:271-82.

26. Barman P, Reddy D, Bhaumik SR. Mechanisms of antisense transcription initiation with implications in gene expression, genomic integrity and disease pathogenesis. Noncoding RNA. 2019;5(1):e11.

27. Weakley SM, Wang H, Yao Q, Chen C. Expression and function of a large non-coding RNA gene XIST in human cancer. World J Surg. 2011;35(8):1751-6.

28. Dandan W, Jianliang C, Haiyan H, Hang M, Xuedong L. Long noncoding RNA MIR31HG is activated by SP1 and promotes cell migration and invasion by sponging miR-214 in NSCLC. Gene. 2019;692:223-30.

29. Brewer CJ, Balen AH. The adverse effect of obesity on conception and implantation. Reproduction. 2010;140(3):347-64.

30. Huang BB, Liu XC, Qin XY, Chen J, Ren PG, Deng WF, et al. Effect of high-fat diet on immature female mice and messenger and noncoding RNA expression profiling in ovary and white adipose tissue. Reprod Sci. 2018.

31. Liu YD, Li Y, Feng SX, Ye DS, Chen X, Zhou XY, et al. Long noncoding RNAs: potential regulators involved in the pathogenesis of polycystic ovary syndrome. Endocrinology. 2017;158(11):3890-9.

32. Moradi MT, Rahimi Z, Vaisi-Raygani A. New insight into the role of long non-coding RNAs in the pathogenesis of preeclampsia. Hypertens Pregnancy. 2019;38(1):41-51.

33. Geisinger A. Spermatogenesis in Mammals: a very peculiar cell differentiation process. Cell Differentiation Research Developments. In: Ivanova LB, editor. New York: Nova Publishers; 2008. p. 97-123.

34. Da Cruz I, Rodríguez-Casuriaga R, Santiñaque FF, Farías J, Curti G, Capoano CA, et al. Transcriptome analysis of highly purified mouse spermatogenic cell populations: gene expression signatures switch from meiotic-to-postmeiotic-related processes at pachytene stage. BMC Genomics. 2016;17:294.

35. Soumillon M, Necsulea A, Weier M, Brawand D, Zhang X, Gu H, et al. Cellular source and mechanisms of high transcriptome complexity in the mammalian testis. Cell Rep. 2013;3(6):2179-90.

36. Necsulea A, Soumillon M, Warnefors M, Liechti A, Daish T, Zeller U, et al. The evolution of lncRNA repertoires and expression patterns in tetrapods. Nature. 2014;505(7485):635-40.

37. Liang M, Li W, Tian H, Hu T, Wang L, Lin Y, et al. Sequential expression of long noncoding RNAs as mRNA gene expression in specific stages of mouse spermatogenesis. Sci Rep. 2014;4:5966.

38. Bao J, Wu J, Schuster AS, Hennig GW, Yan W. Expression profiling reveals developmentally regulated lncRNA repertoire in the mouse male germline. Biol Reprod. 2013;89(5):107.

39. Lin X, Han M, Cheng L, Chen J, Zhang Z, Shen T, et al. Expression dynamics, relationships, and transcriptional regulations of diverse transcripts in mouse spermatogenic cells. RNA Biol. 2016;13(10):1011-24.

40. Wichman L, Somasundaram S, Breindel C, Valerio DM, McCarrey JR, Hodges CA, et al. Dynamic expression of long noncoding RNAs reveals their potential roles in spermatogenesis and fertility. Biol Reprod. 2017;97(2):313-23.

41. Zhu Z, Li C, Yang S, Tian R, Wang J, Yuan Q, et al. Dynamics of the transcriptome during human spermatogenesis: predicting the potential key genes regulating male gametes generation. Sci Rep. 2016;6:19069.

42. Jan SZ, Vormer TL, Jongejan A, Röling MD, Silber SJ, de Rooij DG, et al. Unraveling transcriptome dynamics in human spermatogenesis. Development. 2017;144(20):3659-73.

43. Ran M, Chen B, Li Z, Wu M, Liu X, He C, et al. Systematic identification of long noncoding RNAs in immature and mature porcine testes. Biol Reprod. 2016;94(4):77.

44. Liu Y, Sun Y, Li Y, Bai H, Xue F, Xu S, et al. Analyses of Long Non-Coding RNA and mRNA profiling using RNA sequencing in chicken testis with extreme sperm motility. Sci Rep. 2017;7(1):9055.

45. Akhade VS, Arun G, Donakonda S, Rao MR. Genome wide chromatin occupancy of mrhl RNA and its role in gene regulation in mouse spermatogonial cells. RNA Biol. 2014;11(10):1262-79.

46. Ni MJ, Hu ZH, Liu Q, Liu MF, Lu M, Zhang JS, et al. Identification and characterization of a novel non-coding RNA involved in sperm maturation. Plos One. 2011;6(10):e26053.

47. Anguera MC, Ma W, Clift D, Namekawa S, Kelleher III RJ, Lee JT. Tsx produces a long noncoding RNA and has general functions in the germline, stem cells, and brain. Plos Genet. 2011;7(9):e1002248.

48. Li L, Wang M, Wu X, Geng L, Xue Y, Wei X, et al. A long non-coding RNA interacts with Gfra1 and maintains survival of mouse spermatogonial stem cells. Cell Death Dis. 2016;7:e2140.

49. National Collaborating Centre for Women's and Children's Health. Fertility: Assessment and Treatment for People with Fertility Problems. London: Royal College of Obstetricians & Gynaecologists (UK), 2013.

50. Wang X, Yang C, Guo F, Zhang Y, Ju Z, Jiang Q, et al. Integrated analysis of mRNA and long noncoding RNAs in the semen from Holstein bulls with high and low sperm motility. Sci Rep. 2019;9(1):2092.

51. Zhang X, Zhang P, Song D, Xiong S, Zhang H, Fu J, et al. Expression profiles and characteristics of human lncRNAs in normal and asthenozoospermia sperm. Biol Reprod. 2018;0(0):1-12.

52. An T, Fan H, Liu YF, Pan YY, Liu YK, Mo FF, et al. The difference in expression of long noncoding RNAs in rat semen induced by high-fat diet was associated with metabolic pathways. Peer J. 2017;5:e3518.

53. Znaor A, Lortet-Tieulent J, Jemal A, Bray F. International variations and trends in testicular cancer incidence and mortality. Eur Urol. 2014;65(6):1095-106.

54. Das MK, Furu K, Evensen HF, Haugen ØP, Haugen TB. Knockdown of SPRY4 and SPRY4-IT1 inhibits cell growth and phosphorylation of Akt in human testicular germ cell tumours. Sci Rep. 2018;8(1):2462.

55. Okamoto K. Epigenetics: a way to understand the origin and biology of testicular germ cell tumors. Int J Urol. 2012;19(6):504-11.

56. Ding GL, Liu Y, Liu ME, Pan JX, Guo MX, Sheng JZ, et al. The effects of diabetes on male fertility and epigenetic regulation during spermatogenesis. Asian J Androl. 2015;17(6): 948-53.

57. Jiang GJ, Zhang T, An T, Zhao DD, Yang XY, Zhang DW, et al. Differential expression of long noncoding RNAs between sperm samples from diabetic and non-diabetic mice. Plos One. 2016;11(4):e0154028.

58. Li W, Ning JZ, Cheng F, Yu WM, Rao T, Ruan Y, et al. MALAT1 Promotes cell apoptosis and suppresses cell proliferation in testicular ischemia-reperfusion injury by sponging miR-214 to modulate TRPV4 expression. Cell Physiol Biochem. 2018;46(2):802-14.

59. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab. 2013;88(2):622-6.

60. De Sanctis V, Ciccone S. Fertility preservation in adolescents with Klinefelter’s syndrome. Pediatr Endocrinol Rev. 2010;(Suppl 1):178-81.

61. Winge SB, Dalgaard MD, Jensen JM, Graem N, Schierup MH, Juul A, et al. Transcriptome profiling of fetal Klinefelter testis tissue reveals a possible involvement of long non-coding RNAs in gonocyte maturation. Human Mol Genetics. 2018;27(3):430-9.

62. Salemi M, Cannarella R, Condorelli RA, Cimino L, Ridolfo F, Giurato G, et al. Evidence for long noncoding RNA GAS5 up-regulation in patients with Klinefelter síndrome. BMC Med Genet. 2019;20:4.

63. Dianatpour A, Ghafouri-Fard S. Long non coding RNA expression intersecting cancer and spermatogenesis: a systematic review. Asian Pac J Cancer Prev. 2017;18(10):2601-10.

64. Cheng Z, Lei Z, Yang P, Si A, Xiang D, Zhou J, et al. Long non-coding RNA THOR promotes cell proliferation and metastasis in hepatocellular carcinoma. Gene. 2018;678:129-36.

65. Chen S, Wang L, Sun KX, Xiu Y, Zong ZH, Chen X, et al. The role of long non-coding RNA TDRG1 in epithelial ovarian carcinoma tumorigenesis and progression through miR-93/RhoC pathway. Mol Carcinogenesis. 2017;57(2): 225-34.

66. Miranda-Castro R, de-los-Santos-Álvarez N, Lobo-Castañón MJ. Long noncoding RNAs: from genomic junk to rising stars in the early detection of cancer. Anal Bioanal Chem. 2019;0(0):1-11.

67. Sole C, Arnaiz E, Manterola L, Otaegui D, Lawrie CH. The circulating transcriptome as a source of cancer liquid biopsy biomarkers. Semin Cancer Biol. 2019;pii: S1044-579X(18)30100-7.

68. Sartori DA, Chan DW. Biomarkers in prostate cancer: what’s new? Curr Opin Oncol. 2014;26(3):259-64.

69. Arun G, Diermeir SD, Spector DL. Therapeutic targeting of long non-coding RNAs in cancer. Trends Mol Med. 2018;24(3):257-77.

70. Abudayyeh OO, Gootenberg JS, Essletzbichler P, Han S, Joung J, Belanto JJ, et al. RNA targeting with CRISPR-Cas13a. Nature. 2017;550(7675):280-4.

71. Yoshimura H, Matsuda Y, Yamamoto M, Kamiya S, Ishiwata T. Expression and role of long non-coding RNA H19 in carcinogenesis. Front Biosci. 2018;23:614-25.