Promotor Hypomethylation of TFF1 Gene in Ulcerative Colitis is Positively Correlated with Aging
Abstract
Background: Epigenetic modifications exhibit promising evidence in the etiology and prognosis of important diseases such as inflammatory bowel diseases (IBD). In addition to complex factors involved in IBD, a trend toward better prognosis has been reported in older ages of disease onset, specifically in ulcerative colitis (UC). The gastrointestinal mucous layer is one of the important components that is disturbed in the disease course. The integrity of this layer is maintained with an anti-inflammatory factor called trefoil factors (TFF). We investigated the methylation status of the TFF1 gene in UC patients alongside with correlation of its alteration level with age of disease onset.
Method: We analyzed the promoter methylation status of the TFF1 gene, using the real-time quantitative multiplex methylation specific PCR (QM-MSP). DNA was extracted from colorectal biopsies of 15 ulcerative colitis and 14 healthy controls. Correlation analysis was performed between unmethylated DNA level and age through the Pearson correlation coefficient (PPC) test and simple linear regression models.
Results: Our data provided a significant positive correlation between age and TFF1 hypomethylation in ulcerative colitis patients. However, no significant difference was observed in overall TFF1 methylation status between ulcerative colitis patients and control subjects.
Conclusion: This finding suggests the association between epigenetic upregulation of the TFF1 gene with disease mildness in older patients.
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16. Philippeit C, Busch MDunker N. Epigenetic control of trefoil factor family (TFF) peptide expression in human retinoblastoma cell lines. Cell Physiol Biochem. 2014;34(3):1001-14.
17. Vestergaard EM, Nexo E, Torring N, Borre M, Orntoft TFSorensen KD. Promoter hypomethylation and upregulation of trefoil factors in prostate cancer. Int J Cancer. 2010;127(8):1857-65.
18. Lo PK, Watanabe H, Cheng PC, Teo WW, Liang X, Argani P, et al. MethySYBR, a novel quantitative PCR assay for the dual analysis of DNA methylation and CpG methylation density. J Mol Diagn. 2009;11(5):400-14.
19. Li Y, Deuring J, Peppelenbosch MP, Kuipers EJ, de Haar Cvan der Woude CJ. STAT1, STAT6 and adenosine 3',5'-cyclic monophosphate (cAMP) signaling drive SOCS3 expression in inactive ulcerative colitis. Mol Med. 2012;18(1):1412-9.
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22. Yamasaki S, Sakata Y, Yoshida H, Shirai S, Tanaka Y, Nakano R, et al. Shorter relapse-free period after leukocyte removal therapy in younger than older patients with ulcerative colitis. Digestion. 2019;100(4):247-53.
23. Nakov R, Velikova T, Nakov V, Ianiro G, Gerova VTankova L. Serum trefoil factor 3 predicts disease activity in patients with ulcerative colitis. Eur Rev Med Pharmacol Sci. 2019;23(2):788-94.
24. Longman RJ, Poulsom R, Corfield AP, Warren BF, Wright NAThomas MG. Alterations in the composition of the supramucosal defense barrier in relation to disease severity of ulcerative colitis. J Histochem Cytochem. 2006;54(12):1335-48.
25. Low D, Mizoguchi AMizoguchi E. DNA methylation in inflammatory bowel disease and beyond. World J Gastroenterol. 2013;19(32):5238-49.
26. Koike T, Shimada T, Fujii Y, Chen G, Tabei K, Namatame T, et al. Up-regulation of TFF1 (pS2) expression by TNF-alpha in gastric epithelial cells. J Gastroenterol Hepatol. 2007;22(6):936-42.
27. Muzes G, Molnar B, Tulassay ZSipos F. Changes of the cytokine profile in inflammatory bowel diseases. World J Gastroenterol. 2012;18(41):5848-61.
28. Dossinger V, Kayademir T, Blin NGott P. Down-regulation of TFF expression in gastrointestinal cell lines by cytokines and nuclear factors. Cell Physiol Biochem. 2002;12(4):197-206.
29. Hoffmann W. Trefoil factor family (Tff) peptides and their links to inflammation: A re-evaluation and new medical perspectives. Int J Mol Sci. 2021;22(9):4909.
30. Gonzaga IM, Soares Lima SC, Nicolau MC, Nicolau-Neto P, da Costa NM, de Almeida Simao T, et al. TFF1 hypermethylation and decreased expression in esophageal squamous cell carcinoma and histologically normal tumor surrounding esophageal cells. Clin Epigenetics. 2017;9:130.
31. Rivas-Ortiz CI, Lopez-Vidal Y, Arredondo-Hernandez LJRCastillo-Rojas G. Genetic Alterations in Gastric Cancer Associated with Helicobacter pylori Infection. Front Med (Lausanne). 2017;4:47.
32. Qian Z, Jiang Y, Shou C, Yu J, Huang D, Xie H, et al. Validation of the DNA Methylation Landscape of TFF1/TFF2 in Gastric Cancer. Cancers (Basel). 2022;14(22):5474.
33. Braga Emidio N, Brierley SM, Schroeder CIMuttenthaler M. Structure, Function, and Therapeutic Potential of the Trefoil Factor Family in the Gastrointestinal Tract. ACS Pharmacol Transl Sci. 2020;3(4):583-97.
2. Yi JMKim TO. Epigenetic alterations in inflammatory bowel disease and cancer. Intest Res. 2015;13(2):112-21.
3. Gajendran M, Loganathan P, Jimenez G, Catinella AP, Ng N, Umapathy C, et al. A comprehensive review and update on ulcerative colitis(). Dis Mon. 2019;65(12):100851.
4. Jung MPfeifer GP. Aging and DNA methylation. BMC Biol. 2015;13:7.
5. Duricova D, Burisch J, Jess T, Gower-Rousseau C, Lakatos PLEpiCom E. Age-related differences in presentation and course of inflammatory bowel disease: an update on the population-based literature. J Crohns Colitis. 2014;8(11):1351-61.
6. Roda G, Chien Ng S, Kotze PG, Argollo M, Panaccione R, Spinelli A, et al. Crohn’s disease. Nat Rev Dis Primers. 2020;6(1):22.
7. Boltin D, Perets TT, Vilkin ANiv Y. Mucin function in inflammatory bowel disease: an update. J Clin Gastroenterol. 2013;47(2):106-11.
8. Thim L, Madsen FPoulsen SS. Effect of trefoil factors on the viscoelastic properties of mucus gels. Eur J Clin Invest. 2002;32(7):519-27.
9. Buda A, Jepson MAPignatelli M. Regulatory function of trefoil peptides (TFF) on intestinal cell junctional complexes. Cell Commun Adhes. 2012;19(5-6):63-8.
10. Emidio NB, Hoffmann W, Brierley SMMuttenthaler M. Trefoil factor family: Unresolved questions and clinical perspectives. Trends Biochem Sci 2019;44(5):387-90.
11. Song JY, Kim BW, Lee AW, Lee KY, Chung IS, Lee BI, et al. Expression of MUC5AC and Trefoil Peptide 1 (TFF1) in the Subtypes of Intestinal Metaplasia. Clin Endosc. 2012;45(2):151-4.
12. Cobler L, Mejias-Luque R, Garrido M, Pera M, Badia-Garrido Ede Bolos C. Activation of the NF-kB pathway downregulates TFF-1 in gastric carcinogenesis. Virchows Arch. 2013;463(4):497-507.
13. Wright NA, Poulsom R, Stamp G, Van Norden S, Sarraf C, Elia G, et al. Trefoil peptide gene expression in gastrointestinal epithelial cells in inflammatory bowel disease. Scand J Gastroenterol Suppl. 1992;193:76-82.
14. Alarfaj SJ, Mostafa SA, Negm WA, El-Masry TA, Kamal M, Elsaeed M, et al. Mucosal Genes Expression in Inflammatory Bowel Disease Patients: New Insights. Pharmaceuticals (Basel). 2023;16(2):324.
15. Aamann L, Vestergaard EMGronbaek H. Trefoil factors in inflammatory bowel disease. World J Gastroenterol. 2014;20(12):3223-30.
16. Philippeit C, Busch MDunker N. Epigenetic control of trefoil factor family (TFF) peptide expression in human retinoblastoma cell lines. Cell Physiol Biochem. 2014;34(3):1001-14.
17. Vestergaard EM, Nexo E, Torring N, Borre M, Orntoft TFSorensen KD. Promoter hypomethylation and upregulation of trefoil factors in prostate cancer. Int J Cancer. 2010;127(8):1857-65.
18. Lo PK, Watanabe H, Cheng PC, Teo WW, Liang X, Argani P, et al. MethySYBR, a novel quantitative PCR assay for the dual analysis of DNA methylation and CpG methylation density. J Mol Diagn. 2009;11(5):400-14.
19. Li Y, Deuring J, Peppelenbosch MP, Kuipers EJ, de Haar Cvan der Woude CJ. STAT1, STAT6 and adenosine 3',5'-cyclic monophosphate (cAMP) signaling drive SOCS3 expression in inactive ulcerative colitis. Mol Med. 2012;18(1):1412-9.
20. Schmittgen TDLivak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101-8.
21. Husseiny MI, Kuroda A, Kaye AN, Nair I, Kandeel FFerreri K. Development of a quantitative methylation-specific polymerase chain reaction method for monitoring beta cell death in type 1 diabetes. PLoS One. 2012;7(10):e47942.
22. Yamasaki S, Sakata Y, Yoshida H, Shirai S, Tanaka Y, Nakano R, et al. Shorter relapse-free period after leukocyte removal therapy in younger than older patients with ulcerative colitis. Digestion. 2019;100(4):247-53.
23. Nakov R, Velikova T, Nakov V, Ianiro G, Gerova VTankova L. Serum trefoil factor 3 predicts disease activity in patients with ulcerative colitis. Eur Rev Med Pharmacol Sci. 2019;23(2):788-94.
24. Longman RJ, Poulsom R, Corfield AP, Warren BF, Wright NAThomas MG. Alterations in the composition of the supramucosal defense barrier in relation to disease severity of ulcerative colitis. J Histochem Cytochem. 2006;54(12):1335-48.
25. Low D, Mizoguchi AMizoguchi E. DNA methylation in inflammatory bowel disease and beyond. World J Gastroenterol. 2013;19(32):5238-49.
26. Koike T, Shimada T, Fujii Y, Chen G, Tabei K, Namatame T, et al. Up-regulation of TFF1 (pS2) expression by TNF-alpha in gastric epithelial cells. J Gastroenterol Hepatol. 2007;22(6):936-42.
27. Muzes G, Molnar B, Tulassay ZSipos F. Changes of the cytokine profile in inflammatory bowel diseases. World J Gastroenterol. 2012;18(41):5848-61.
28. Dossinger V, Kayademir T, Blin NGott P. Down-regulation of TFF expression in gastrointestinal cell lines by cytokines and nuclear factors. Cell Physiol Biochem. 2002;12(4):197-206.
29. Hoffmann W. Trefoil factor family (Tff) peptides and their links to inflammation: A re-evaluation and new medical perspectives. Int J Mol Sci. 2021;22(9):4909.
30. Gonzaga IM, Soares Lima SC, Nicolau MC, Nicolau-Neto P, da Costa NM, de Almeida Simao T, et al. TFF1 hypermethylation and decreased expression in esophageal squamous cell carcinoma and histologically normal tumor surrounding esophageal cells. Clin Epigenetics. 2017;9:130.
31. Rivas-Ortiz CI, Lopez-Vidal Y, Arredondo-Hernandez LJRCastillo-Rojas G. Genetic Alterations in Gastric Cancer Associated with Helicobacter pylori Infection. Front Med (Lausanne). 2017;4:47.
32. Qian Z, Jiang Y, Shou C, Yu J, Huang D, Xie H, et al. Validation of the DNA Methylation Landscape of TFF1/TFF2 in Gastric Cancer. Cancers (Basel). 2022;14(22):5474.
33. Braga Emidio N, Brierley SM, Schroeder CIMuttenthaler M. Structure, Function, and Therapeutic Potential of the Trefoil Factor Family in the Gastrointestinal Tract. ACS Pharmacol Transl Sci. 2020;3(4):583-97.
| Files | ||
| Issue | Vol 6, No 2 (2023) | |
| Section | Original Article | |
| DOI | https://doi.org/10.18502/igj.v6i2.16412 | |
| Keywords | ||
| Inflammatory Bowel Disease Ulcerative Colitis Trefoil Factor Epigenetics Methylation Aging | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Hemmati S, Sanati G, Sadeghi MA, Ebrahimi Daryani N, Rezaei N. Promotor Hypomethylation of TFF1 Gene in Ulcerative Colitis is Positively Correlated with Aging. Immunol Genet J. 2023;6(2):79-86.
