Abnormal Promoter Methylation of Nucleotide-Binding Oligomerization Domain Containing 2 (NOD2) Gene in the Pathogenesis of Crohn’s Disease
-
Golshid Sanati
,
Mehrdad Noruzinia
,
Davood Jafari
,
Mohammad Ahmadvand
,
Shahram Teimourian
,
Naser Ebrahimi Daryani
,
Nima Rezaei
Abstract
Changes in the expression of nucleotide-binding oligomerization domain containing 2 (NOD2) play an important role in the pathogenesis of several autoimmune diseases, such as inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). It seems that epigenetic modifications, including DNA methylation, have an important role in the suppression of gene activity. In this study, the relationship between DNA methylation patterns of the promoter region of the NOD2 gene and the pathogenesis of CD was assessed. Colonic mucosal samples were obtained from 15 Iranian patients with CD and 15 matched healthy controls with no history of autoimmune diseases. After bisulfite conversion of genomic DNA, the DNA methylation status of three CpG sites in the promoter region of the NOD2 gene was determined by the real-time quantitative multiplex methylation-specific PCR assay. Using this approach, we identified a decreased level of methylation of the NOD2 promoter in the colonic mucosa of patients with CD (0.128±0.093 vs. 0.025±0.016, unmethylated DNA in CD vs. healthy controls, respectively, P<0.000). According to our findings, promoter hypomethylation of the NOD2 gene in the colonic mucosa might contribute to the development and severity of CD.
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19. Saito S, Kato J, Hiraoka S, Horii J, Suzuki H, Higashi R, et al. DNA methylation of colon mucosa in ulcerative colitis patients: correlation with inflammatory status. Inflamm Bowel Dis 2011;17:1955-65.
20. Scarpa M, Stylianou E. Epigenetics: concepts and relevance to IBD pathogenesis. Inflamm Bowel Dis 2012. 18:1982-96.
21. Kellermayer R, Balasa A, Zhang W, Lee S, Mirza S, Chakravarty A, et al., Epigenetic maturation in colonic mucosa continues beyond infancy in mice. Hum Mol Genet 2010;19:2168-76.
22. Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human diseases. Biochim Biophys Acta 2007;1775:138-62.
23. Lee JC, Parkes M. Genome-wide association studies and Crohn’s disease. Brief Funct Genomics 2011;10:71-6.
24. Yamada Y, Nishida T, Horibe H, Oguri M, Kato K, Sawabe M. Identification of hypo-and hypermethylated genes related to atherosclerosis by a genome-wide analysis of DNA methylation. Int J mol Med 2014;33:1355-40.
2. Kim SW, Kim ES, Moon CM, Kim TI, Kim WH, Cheon JH. Abnormal genetic and epigenetic changes in signal transducer and activator of transcription 4 in the pathogenesis of inflammatory bowel diseases. Dig Dis Sci 2012;57:2600-7.
3. Cheon J, Kim S, Jeon S, Kim T, Kim W. Associations of genetic polymorphisms and epigenetic changes in interleukin 17A and interleukin 23 receptor with inflammatory bowel disease. P‐029. Inflamm Bowel Dis 2011;17:S21.
4. Nielsen HM, Tost J. Epigenetic changes in inflammatory and autoimmune diseases. In: Kundu TK, eds. Epigenetics: Development and Disease. Springer; 2013:455-78.
5. Bäckdahl LA. Bushell A, Beck S. Inflammatory signalling as mediator of epigenetic modulation in tissue-specific chronic inflammation. Int J Biochem Cell Biol 2009;41:176-84.
6. Petronis A, Petroniene R. Epigenetics of inflammatory bowel disease. Gut 2000;47:302-6.
7. Lin Z, Hegarty JP, Yu W, Cappel JA, Chen X, Faber PW, et al. Identification of disease-associated DNA methylation in B cells from Crohn’s disease and ulcerative colitis patients. Dig Dis Sci 2012;57:3145-53.
8. Cooke J, Zhang H, Greger L, Silva AL, Massey D, Dawson C, et al. Mucosal genome‐wide methylation changes in inflammatory bowel disease. Inflamm Bowel Dis 2012;18:2128-37.
9. Lin Z, Hegarty JP, Cappel JA, Yu W, Chen X, Faber P, et al. Identification of disease‐associated DNA methylation in intestinal tissues from patients with inflammatory bowel disease. Clin Genet 2011;80:59-67.
10. Hartnett L, Egan LJ. Inflammation, DNA methylation and colitis-associated cancer. Carcinogenesis 2012;33:723-31.
11. Gonsky R, Deem RL, Landers CJ, Derkowski CA, Berel D, McGovern DP, et al., Distinct IFNG methylation in a subset of ulcerative colitis patients based on reactivity to microbial antigens. Inflamm Bowel Dis 2011;17:171-8.
12. Cho JH. Inflammatory bowel disease: genetic and epidemiologic considerations. World J Gastroenterol 2008;14:338-47.
13. Strober W, Watanabe T. NOD2, an intracellular innate immune sensor involved in host defense and Crohn's disease. Mucosal Immunol 2011;4:484-95.
14. Berrebi D, Maudinas R, Hugot JP, Chamaillard M, Chareyre F, De Lagausie P, et al. Card15 gene overexpression in mononuclear and epithelial cells of the inflamed Crohn’s disease colon. Gut 2003;52:840-6.
15. 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;11:400-14.
16. Li, Y, Deuring J, Peppelenbosch MP, Kuipers EJ, de Haar C, van der Woude CJ. IL-6-induced DNMT1 activity mediates SOCS3 promoter hypermethylation in ulcerative colitis-related colorectal cancer. Carcinogenesis 2012;33:1889-96.
17. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc 2008;3:1101-8.
18. Husseiny MI, Kuroda A, Kaye AN, Nair I, Kandeel F, Ferreri K. Development of a quantitative methylation-specific polymerase chain reaction method for monitoring beta cell death in type 1 diabetes. PloS One 2012;7:e47942.
19. Saito S, Kato J, Hiraoka S, Horii J, Suzuki H, Higashi R, et al. DNA methylation of colon mucosa in ulcerative colitis patients: correlation with inflammatory status. Inflamm Bowel Dis 2011;17:1955-65.
20. Scarpa M, Stylianou E. Epigenetics: concepts and relevance to IBD pathogenesis. Inflamm Bowel Dis 2012. 18:1982-96.
21. Kellermayer R, Balasa A, Zhang W, Lee S, Mirza S, Chakravarty A, et al., Epigenetic maturation in colonic mucosa continues beyond infancy in mice. Hum Mol Genet 2010;19:2168-76.
22. Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human diseases. Biochim Biophys Acta 2007;1775:138-62.
23. Lee JC, Parkes M. Genome-wide association studies and Crohn’s disease. Brief Funct Genomics 2011;10:71-6.
24. Yamada Y, Nishida T, Horibe H, Oguri M, Kato K, Sawabe M. Identification of hypo-and hypermethylated genes related to atherosclerosis by a genome-wide analysis of DNA methylation. Int J mol Med 2014;33:1355-40.
| Files | ||
| Issue | Vol 61 No 5 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/acta.v61i5.13480 | |
| Keywords | ||
| Nucleotide-binding oligomerization domain containing 2 (NOD2) Inflammatory bowel disease Crohn’s disease DNA methylation | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Sanati G, Noruzinia M, Jafari D, Ahmadvand M, Teimourian S, Ebrahimi Daryani N, Rezaei N. Abnormal Promoter Methylation of Nucleotide-Binding Oligomerization Domain Containing 2 (NOD2) Gene in the Pathogenesis of Crohn’s Disease. Acta Med Iran. 2023;61(5):264-269.
