A Functional Variable Number of Tandem Repeats is Located at the 5′ Flanking Region of the Human Secretin Gene Plays a Downregulatory Role in Expression

  • Leo T. O. Lee
  • Ian P. Y. Lam
  • Billy K. C. Chow
Article

Abstract

Secretin is a peptide hormone playing multiple functions in the brain–gut axis. In this report, we investigated, by promoter analysis, the potential function of the variable of tandem repeats (VNTR), located at the 5′ upstream region of the human secretin gene, and we demonstrated for the first time that this VNTR could downregulate transcription of the human secretin gene in a promoter-specific manner. The efficiency of VNTR in silencing the promoter was found to be directly related the number of repetitive units residing within. We also showed the deoxyribonucleic acid sequence as well as the length polymorphism of the VNTR of 76 Chinese individuals. These results collectively suggest that VNTR could potentially be a functional regulator to control the expression of the human secretin gene in different individuals.

Keywords

Secretin Variable number of tandem repeats Gene expression 

References

  1. Ariano, M. A., Wang, J., Noblett, K. L., Larson, E. R., & Sibley, D. R. (1997). Cellular distribution of the rat D4 dopamine receptor protein in the CNS using anti-receptor antisera. Brain Research, 752, 26–34.PubMedCrossRefGoogle Scholar
  2. Catasti, P., Chen, X., Mariappan, S. V., Bradbury, E. M., & Gupta, G. (1999). DNA repeats in the human genome. Genetica, 106, 15–36.PubMedCrossRefGoogle Scholar
  3. Chang, F. M., Kidd, J. R., Livak, K. J., Pakstis, A. J., & Kidd, K. K. (1996). The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus. Human Genetics, 98, 91–101.PubMedCrossRefGoogle Scholar
  4. Chevalier, D., et al. (2001). Characterization of new mutations in the coding sequence and 5¢-untranslated region of the human prostacylcin synthase gene (CYP8A1). Human Genetics, 108, 148–155.PubMedCrossRefGoogle Scholar
  5. Chey, W. Y., & Chang, T. M. (2003). Secretin, 100 years later. Journal of Gastroenterology, 38, 1025–1035.PubMedCrossRefGoogle Scholar
  6. Guo, G., Ou, X. M., Roettger, M., & Shih, J. C. (2008). The VNTR 2 repeat in MAOA and delinquent behavior in adolescence and young adulthood: Associations and MAOA promoter activity. European Journal of Human Genetics, 16, 626–634.PubMedCrossRefGoogle Scholar
  7. Iwashita, S., Koyama, K., & Nakamura, Y. (2001). VNTR sequence on human chromosome 11p15 that affects transcriptional activity. Journal of Human Genetics, 46, 717–721.PubMedCrossRefGoogle Scholar
  8. Lakatos, K., et al. (2003). Association of D4 dopamine receptor gene and serotonin transporter promoter polymorphisms with infants’ response to novelty. Molecular Psychiatry, 8, 90–97.PubMedCrossRefGoogle Scholar
  9. Lam, I. P., Siu, F. K., Chu, J. Y., & Chow, B. K. (2008). Multiple actions of secretin in the human body. International Review of Cytology, 265, 159–190.PubMedCrossRefGoogle Scholar
  10. Lee, K. A., Bindereif, A., & Green, M. R. (1988). A small-scale procedure for preparation of nuclear extracts that support efficient transcription and pre-mRNA splicing. Gene Analysis Techniques, 5, 22–31.PubMedCrossRefGoogle Scholar
  11. Lee, L. T., Tan-Un, K. C., Pang, R. T., Lam, D. T., & Chow, B. K. (2004). Regulation of the human secretin gene is controlled by the combined effects of CpG methylation, Sp1/Sp3 ratio, and the E-box element. Molecular Endocrinology, 18, 1740–1755.PubMedCrossRefGoogle Scholar
  12. Lee, S. M., Chen, L., Chow, B. K., & Yung, W. H. (2005). Endogenous release and multiple actions of secretin in the rat cerebellum. Neuroscience, 134, 377–386.PubMedCrossRefGoogle Scholar
  13. Lindstedt, B. A., Ryberg, D., Zienolddiny, S., Khan, H., & Haugen, A. (1999). Hras1 VNTR alleles as susceptibility markers for lung cancer: Relationship to microsatellite instability in tumors. Anticancer Research, 19, 5523–5527.PubMedGoogle Scholar
  14. Meador-Woodruff, J. H., et al. (1994). Dopamine receptor gene expression in the human medial temporal lobe. Neuropsychopharmacology, 10, 239–248.PubMedGoogle Scholar
  15. Mrzljak, L., Bergson, C., Pappy, M., Huff, R., Levenson, R., & Goldman-Rakic, P. S. (1996). Localization of dopamine D4 receptors in GABAergic neurons of the primate brain. Nature, 381, 245–248.PubMedCrossRefGoogle Scholar
  16. Mutoh, H., Fung, B. P., Naya, F. J., Tsai, M. J., Nishitani, J., & Leiter, A. B. (1997). The basic helix–loop–helix transcription factor BETA2/NeuroD is expressed in mammalian enteroendocrine cells and activates secretin gene expression. Proceedings of the National Academy of Sciences of United States of America, 94, 3560–3564.CrossRefGoogle Scholar
  17. Mutoh, H., Naya, F. J., Tsai, M. J., & Leiter, A. B. (1998). The basic helix–loop–helix protein BETA2 interacts with p300 to coordinate differentiation of secretin-expressing enteroendocrine cells. Genes & Development, 12, 820–830.CrossRefGoogle Scholar
  18. Myers, K., Goulet, M., Rusche, J., Boismenu, R., & Davis, M. (2004). Inhibition of fear potentiated startle in rats following peripheral administration of secretin. Psychopharmacology (Berl), 172, 94–99.CrossRefGoogle Scholar
  19. Nelson, R. M., & Long, G. L. (1989). A general method of site-specific mutagenesis using a modification of the Thermus aquaticus polymerase chain reaction. Analytical Biochemistry, 180, 147–151.PubMedCrossRefGoogle Scholar
  20. Ng, S. S., Yung, W. H., & Chow, B. K. (2002). Secretin as a neuropeptide. Molecular Neurobiology, 26, 97–107.PubMedCrossRefGoogle Scholar
  21. Nishijima, I., et al. (2006). Secretin receptor-deficient mice exhibit impaired synaptic plasticity and social behavior. Human Molecular Genetics, 15, 3241–3250.PubMedCrossRefGoogle Scholar
  22. Sabol, S. Z., Hu, S., & Hamer, D. (1998). A functional polymorphism in the monoamine oxidase A gene promoter. Human Genetics, 103, 273–279.PubMedCrossRefGoogle Scholar
  23. Schoots, O., & Van Tol, H. H. (2003). The human dopamine D4 receptor repeat sequences modulate expression. Pharmacogenomics Journal, 3, 343–348.PubMedCrossRefGoogle Scholar
  24. Tovar, D., Faye, J. C., & Favre, G. (2003). Cloning of the human RHOB gene promoter: Characterization of a VNTR sequence that affects transcriptional activity. Genomics, 81, 525–530.PubMedCrossRefGoogle Scholar
  25. Trepicchio, W. L., & Krontiris, T. G. (1992). Members of the rel/NF-kappa B family of transcriptional regulatory proteins bind the HRAS1 minisatellite DNA sequence. Nucleic Acids Research, 20, 2427–2434.PubMedCrossRefGoogle Scholar
  26. Weitzel, J. N., et al. (2000). The HRAS1 minisatellite locus and risk of ovarian cancer. Cancer Res, 60, 259–261.PubMedGoogle Scholar
  27. Welch, M. G., Keune, J. D., Welch-Horan, T. B., Anwar, N., Anwar, M., & Ruggiero, D. A. (2003). Secretin activates visceral brain regions in the rat including areas abnormal in autism. Cellular and Molecular Neurobiology, 23, 817–837.PubMedCrossRefGoogle Scholar
  28. Whitmore, T. E., et al. (2000). Human secretin (SCT): Gene structure, chromosome location, and distribution of mRNA. Cytogenetics and Cell Genetics, 90, 47–52.PubMedCrossRefGoogle Scholar
  29. Yamagata, T., Aradhya, S., Mori, M., Inoue, K., Momoi, M. Y., & Nelson, D. L. (2002). The human secretin gene: Fine structure in 11p15.5 and sequence variation in patients with autism. Genomics, 80, 185–194.PubMedCrossRefGoogle Scholar
  30. Yung, W. H., Leung, P. S., Ng, S. S., Zhang, J., Chan, S. C., & Chow, B. K. (2001). Secretin facilitates GABA transmission in the cerebellum. Journal of Neuroscience, 21, 7063–7068.PubMedGoogle Scholar

Copyright information

© Humana Press 2008

Authors and Affiliations

  • Leo T. O. Lee
    • 1
  • Ian P. Y. Lam
    • 1
  • Billy K. C. Chow
    • 1
  1. 1.School of Biological SciencesThe University of Hong KongHong KongChina

Personalised recommendations