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Functional implications of the CpG island methylation in the pathogenesis of celiac disease

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Abstract

Investigation of gene-environment cross talk through epigenetic modifications led to better understanding of the number of complex diseases. Clinical heterogeneity and differential treatment response often contributed by the epigenetic signatures which could be personal. DNA methylation at CpG islands presents a critical nuclear process as a result of gene-environment interactions. These CpG islands are frequently present near the promoter sequence of genes and get differentially methylated under specific environmental conditions. Technical advancements facilitate in high throughput screening of differentially methylated CpG islands. Recent epigenetic studies unraveled several CD susceptibility genes expressed in peripheral blood lymphocytes (PBLs), duodenal mucosa, lamina and epithelial cells that are influenced by differentially methylated CpG islands. Here we highlighted these susceptibility genes; classify these genes based on cellular functions and tissue of expression. We further discussed how these genes interacts with each other to influence critical pathways like NF-κB signaling pathway, IL-17 signaling cascade, RIG-I like receptor signaling pathway, NOD-like receptor pathways among several others. This review also shed light on how gut microbiota may lead to the differential methylation of CpG islands of CD susceptibility genes. Large scale epigenetic studies followed by estimation of heritability of these CpG methylation and polygenic risk score estimation of these genes would prioritize potentially druggable targets for better therapeutics. In vivo studies are warranted to unravel further cellular responses to CpG methylation.

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References

  1. Rubio-Tapia A, Ludvigsson JF, Brantner TL, Murray JA, Everhart JE (2012) The prevalence of celiac disease in the United States. Am J Gastroenterol 107:1538–1544

    Article  PubMed  Google Scholar 

  2. Larson SA, Khaleghi S, Rubio-Tapia A, Ovsyannikova IG, King KS, Larson JJ, Lahr BD, Poland GA, Camilleri MJ, Murray JA (2017) Prevalence and morbidity of undiagnosed celiac disease from a community-based study. Gastroenterology 152(4):830–839

    Article  PubMed  Google Scholar 

  3. Shan L, Molberg Ø, Parrot I, Hausch F, Filiz F, Gray GM, Sollid LM, Khosla C (2002) Structural basis for gluten intolerance in celiac sprue. Science 297(5590):2275–2279

    Article  CAS  PubMed  Google Scholar 

  4. Shan L, Qiao SW, Arentz-Hansen H, Molberg Ø, Gray GM, Sollid LM, Khosla C (2005) Identification and analysis of multivalent proteolytically resistant peptides from gluten: implications for celiac sprue. J Proteome Res 4(5):1732–1741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cebolla Á, Moreno MD, Coto L, Sousa C (2018) Gluten immunogenic peptides as standard for the evaluation of potential harmful prolamin content in food and human specimen. Nutrients 10(12):1927

    Article  PubMed Central  Google Scholar 

  6. Abadie V, Kim SM, Lejeune T, Palanski BA, Ernest JD, Tastet O, Voisine J, Discepolo V, Marietta EV, Hawash MBF, Ciszewski C, Bouziat R, Panigrahi K, Horwath I, Zurenski MA, Lawrence I, Dumaine A, Yotova V, Grenier JC, Murray JA, Khosla C, Barreiro LB, Jabri B (2020) IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease. Nature 578(7796):600–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Auricchio R, Mandile R, Del Vecchio MR, Scapaticci S, Galatola M, Maglio M, Discepolo V, Miele E, Cielo D, Troncone R, Greco L (2019) Progression of celiac disease in children with antibodies against tissue transglutaminase and normal duodenal architecture. Gastroenterology 157(2):413–420

    Article  PubMed  Google Scholar 

  8. Kav T, Tseveldorj N, Ozcimen B, Tan C, Sivri B (2021) Human leucocyte antigen genotyping in celiac disease: reasons for inappropriate use. Clin Lab. https://doi.org/10.7754/Clin.Lab.2021.210128

    Article  PubMed  Google Scholar 

  9. Van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M, Wapenaar MC, Barnardo MC, Bethel G, Holmes GK, Feighery C (2007) A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 39(7):827–829

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fernandez-Jimenez N, Garcia-Etxebarria K, Plaza-Izurieta L, Romero-Garmendia I, Jauregi-Miguel A, Legarda M, Ecsedi S, Castellanos-Rubio A, Cahais V, Cuenin C, DegliEsposti D (2019) The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region. Sci Rep 9(1):1–3

    Article  CAS  Google Scholar 

  11. Cielo D, Galatola M, Fernandez-Jimenez N, De Leo L, Garcia-Etxebarria K, Loganes C, Tommasini A, Not T, Auricchio R, Greco L, Bilbao JR (2019) Combined analysis of methylation and gene expression profiles in separate compartments of small bowel mucosa identified celiac disease patients’ signatures. Sci Rep 9(1):1–2

    Article  CAS  Google Scholar 

  12. McDermott E, Ryan EJ, Tosetto M, Gibson D, Burrage J, Keegan D, Byrne K, Crowe E, Sexton G, Malone K, Harris RA (2016) DNA methylation profiling in inflammatory bowel disease provides new insights into disease pathogenesis. J Crohns Colitis 10(1):77–86

    Article  PubMed  Google Scholar 

  13. Agardh E, Lundstig A, Perfilyev A, Volkov P, Freiburghaus T, Lindholm E, Rönn T, Agardh CD, Ling C (2015) Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy. BMC Med 13(1):182

    Article  PubMed  PubMed Central  Google Scholar 

  14. Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11(10):726–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shaw R (2006) The epigenetics of oral cancer. Int J Oral Maxillofac Surg 35(2):101–108

    Article  CAS  PubMed  Google Scholar 

  16. Bergmann F, Singh S, Michel S, Kahlert C, Schirmacher P, Helmke B, Von KnebelDoeberitz M, Kloor M, Bläker H (2010) Small bowel adenocarcinomas in celiac disease follow the CIM-MSI pathway. Oncol Rep 24(6):1535–1539

    CAS  PubMed  Google Scholar 

  17. Shi J, Xu J, Chen YE, Li JS, Cui Y, Shen L, Li JJ, Li W (2021) The concurrence of DNA methylation and demethylation is associated with transcription regulation. Nat Commun 12(1):5285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fernandez-Jimenez N, Castellanos-Rubio A, Plaza-Izurieta L, Irastorza I, Elcoroaristizabal X, Jauregi-Miguel A, Lopez-Euba T, Tutau C, de Pancorbo MM, Vitoria JC, Bilbao JR (2014) Coregulation and modulation of NFκB-related genes in celiac disease: uncovered aspects of gut mucosal inflammation. Hum Mol Genet 23(5):1298–1310

    Article  CAS  PubMed  Google Scholar 

  19. Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13(7):484–492

    Article  CAS  PubMed  Google Scholar 

  20. Deaton AM, Webb S, Kerr AR, Illingworth RS, Guy J, Andrews R, Bird A (2011) Cell type–specific DNA methylation at intragenic CpG islands in the immune system. Genome Res 21(7):1074–1086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Saxonov S, Berg P, Brutlag DL (2006) A genome-wide analysis of CpGdinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci USA 103(5):1412–1417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Carninci P, Sandelin A, Lenhard B, Katayama S, Shimokawa K, Ponjavic J, Semple CA, Taylor MS, Engström PG, Frith MC, Forrest AR (2006) Genome-wide analysis of mammalian promoter architecture and evolution. Nat Genet 38(6):626–635

    Article  CAS  PubMed  Google Scholar 

  23. Angrisano T, Pero R, Peluso S, Keller S, Sacchetti S, Bruni CB, Chiariotti L, Lembo F (2010) LPS-induced IL-8 activation in human intestinal epithelial cells is accompanied by specific histone H3 acetylation and methylation changes. BMC Microbiol 10(1):172

    Article  PubMed  PubMed Central  Google Scholar 

  24. Deaton AM, Bird A (2011) CpG islands and the regulation of transcription. Genes Dev 25:1010–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hansen KD, Timp W, Bravo HC, Sabunciyan S, Langmead B, McDonald OG, Wen B, Wu H, Liu Y, Diep D, Briem E (2011) Increased methylation variation in epigenetic domains across cancer types. Nat Genet 43(8):768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. DegliEsposti D, Sklias A, Lima SC, Beghelli-de Forest la S, Cahais V, Fernandez-Jimenez N, Cros MP, Ecsedi S, Cuenin C, Bouaoun L, Byrnes G (2017) Unique DNA methylation signature in HPV-positive head and neck squamous cell carcinomas. Genome Med 9(1):33

    Article  Google Scholar 

  27. Abitew AM, Sobti RC, Sharma VL, Wanchu A (2020) Analysis of transporter associated with antigen presentation (TAP) genes polymorphisms with HIV-1 infection. Mol Cell Biochem 464(1–2):65–71

    Article  CAS  PubMed  Google Scholar 

  28. Kurokohchi K, Carrington M, Mann DL, Simonis TB, Alexander-Miller MA, Feinstone SM, Akatsuka T, Berzofsky JA (1996) Expression of HLA class I molecules and the transporter associated with antigen processing in hepatocellular carcinoma. Hepatology 23(5):1181–1188

    Article  CAS  PubMed  Google Scholar 

  29. Cromme FV, Airey J, Heemels MT, Ploegh HL, Keating PJ, Stern PL, Meijer CJ, Walboomers JM (1994) Loss of transporter protein, encoded by the TAP-1 gene, is highly correlated with loss of HLA expression in cervical carcinomas. J Exp Med 179(1):335–340

    Article  CAS  PubMed  Google Scholar 

  30. Devallière J, Charreau B (2011) The adaptor Lnk (SH2B3): an emerging regulator in vascular cells and a link between immune and inflammatory signaling. Biochem Pharmacol 82(10):1391–1402

    Article  PubMed  Google Scholar 

  31. Takizawa H, Kubo-Akashi C, Nobuhisa I, Kwon SM, Iseki M, Taga T, Takatsu K, Takaki S (2006) Enhanced engraftment of hematopoietic stem/progenitor cells by the transient inhibition of an adaptor protein, Lnk. Blood 107(7):2968–2975

    Article  CAS  PubMed  Google Scholar 

  32. Escudero-Hernández C, Plaza-Izurieta L, Garrote JA, Bilbao JR, Arranz E (2017) Association of the IL-15 and IL-15Rα genes with celiac disease. Cytokine 9(9):73–79

    Article  Google Scholar 

  33. Di Sabatino A, Ciccocioppo R, Cupelli F, Cinque B, Millimaggi D, Clarkson MM, Paulli M, Cifone MG, Corazza GR (2006) Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease. Gut 55(4):469–477

    Article  PubMed  PubMed Central  Google Scholar 

  34. Doi K, Ishikura S, Shirasawa S (2014) The roles of ZFAT in thymocyte differentiation and homeostasis of peripheral naive T-cells. Anticancer Res 34(8):4489–4495

    CAS  PubMed  Google Scholar 

  35. Fernandez-Jimenez N, Bilbao JR (2019) Mendelian randomization analysis of celiac GWAS reveals a blood expression signature with diagnostic potential in absence of gluten consumption. Hum Mol Genet 28(18):3037–3042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Imgenberg-Kreuz J, Almlöf JC, Leonard D, Alexsson A, Nordmark G, Eloranta ML, Rantapää-Dahlqvist S, Bengtsson AA, Jönsen A, Padyukov L, Gunnarsson I (2018) DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus. Ann Rheum Dis 77(5):736–743

    Article  CAS  PubMed  Google Scholar 

  37. Peery RC, Pammi M, Claud E, Shen L (2021) Epigenome—a mediator for host-microbiome crosstalk. Semin Perinatol 45(6):151455

    Article  PubMed  Google Scholar 

  38. Round JL, Mazmanian SK (2009) The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9(5):313–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Szebeni B, Veres G, Dezsofi A, Rusai K, Vannay Á, Bokodi G, Vásárhelyi B, Korponay-Szabó IR, Tulassay T, Arató A (2007) Increased mucosal expression of Toll-like receptor (TLR) 2 and TLR4 in coeliac disease. J Pediatr Gastroenterol Nutr 45(2):187–193

    Article  CAS  PubMed  Google Scholar 

  40. Ashida H, Ogawa M, Kim M, Mimuro H, Sasakawa C (2012) Bacteria and host interactions in the gut epithelial barrier. Nat Chem Biol 8(1):36

    Article  CAS  Google Scholar 

  41. Stappenbeck TS, Hooper LV, Gordon JI (2002) Developmental regulation of intestinal angiogenesis by indigenous microbes via Panethcells. Proc Natl Acad Sci 99(24):15451–15455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Galipeau HJ, McCarville JL, Huebener S, Litwin O, Meisel M, Jabri B, Sanz Y, Murray JA, Jordana M, Alaedini A, Chirdo FG (2015) Intestinal microbiota modulates gluten-induced immunopathology in humanized mice. Am J Pathol 185(11):2969–2982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nadal I, Donant E, Ribes-Koninckx C, Calabuig M, Sanz Y (2007) Imbalance in the composition of the duodenal microbiota of children with coeliac disease. J Med Microbiol 56(12):1669–1674

    Article  CAS  PubMed  Google Scholar 

  44. Collado MC, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y (2008) Imbalances in faecal and duodenal Bifidobacterium species composition in active and non-active coeliac disease. BMC Microbiol 8(1):232

    Article  PubMed  PubMed Central  Google Scholar 

  45. Collado MC, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y (2009) Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. J Clin Pathol 62(3):264–269

    Article  CAS  PubMed  Google Scholar 

  46. Lasa J, Zubiaurre I, Dima G, Peralta D, Soifer L (2015) Helicobacterpylori prevalence in patients with celiac disease: results from across-sectional study. Arq Gastroenterol 52:139–142

    Article  PubMed  Google Scholar 

  47. Lebwohl B, Blaser MJ, Ludvigsson JF et al (2013) Decreased risk ofceliac disease in patients with Helicobacter pylori colonization. Am J Epidemiol 178:1721–1730

    Article  PubMed  PubMed Central  Google Scholar 

  48. Simondi D, Ribaldone DG, Bonagura GA et al (2015) Helicobacter pylori in celiac disease and in duodenal intraepithelial lymphocytosis: active protagonist or innocent bystander? Clin Res Hepatol Gastroenterol 39:740–745

    Article  PubMed  Google Scholar 

  49. Jozefczuk J, Bancerz B, Walkowiak M et al (2015) Prevalence of helicobacter pylori infection in pediatric celiac disease. Eur Rev Med Pharmacol Sci 19:2031–2035

    CAS  PubMed  Google Scholar 

  50. Bouziat R, Hinterleitner R, Brown JJ, Stencel-Baerenwald JE, Ikizler M, Mayassi T, Meisel M, Kim SM, Discepolo V, Pruijssers AJ, Ernest JD (2017) Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease. Science 356(6333):44–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lakhdari O, Cultrone A, Tap J, Gloux K, Bernard F, Ehrlich SD, Lefèvre F, Doré J, Blottière HM (2010) Functional metagenomics: a high throughput screening method to decipher microbiota-driven NF-κB modulation in the human gut. PLoS ONE. https://doi.org/10.1371/journal.pone.0013092

    Article  PubMed  PubMed Central  Google Scholar 

  52. De Palma G, Capilla A, Nova E, Castillejo G, Varea V, Pozo T, Garrote JA, Polanco I, López A, Ribes-Koninckx C, Marcos A (2012) Influence of milk-feeding type and genetic risk of developing coeliac disease on intestinal microbiota of infants: the PROFICEL study. PLoS ONE. https://doi.org/10.1371/journal.pone.0030791

    Article  PubMed  PubMed Central  Google Scholar 

  53. Zhernakova A, Elbers CC, Ferwerda B, Romanos J, Trynka G, Dubois PC, De Kovel CG, Franke L, Oosting M, Barisani D, Bardella MT (2010) Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection. Am J Human Genet 86(6):970–977

    Article  CAS  Google Scholar 

  54. Pietz G, De R, Hedberg M, Sjöberg V, Sandström O, Hernell O, Hammarström S, Hammarström ML (2017) Immunopathology of childhood celiac disease-key role of intestinal epithelial cells. PLoS ONE 12(9):e0185025

    Article  PubMed  PubMed Central  Google Scholar 

  55. Mendes V, Galvao I, Vieira AT (2019) Mechanisms by which the gut microbiota influences cytokine production and modulates host inflammatory responses. J Interferon Cytokine Res 39(7):393–409

    Article  CAS  PubMed  Google Scholar 

  56. Hayden MS, Ghosh S (2011) NF-kB in immunology. Cell Res 21(2):223–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Stone KP, Kastin AJ, Pan W (2011) NFĸB is an unexpected major mediator of interleukin-15 signaling in cerebral endothelia. Cell Physiol Biochem 28(1):115–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sapone A, Lammers KM, Mazzarella G, Mikhailenko I, Cartenì M, Casolaro V, Fasano A (2010) Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease. Int Arch Allergy Immunol 152(1):75–80

    Article  CAS  PubMed  Google Scholar 

  59. Castellanos-Rubio A, Santin I, Irastorza I, Castaño L, Carlos Vitoria J, Ramon BJ (2009) TH17 (and TH1) signatures of intestinal biopsies of CD patients in response to gliadin. Autoimmunity 42(1):69–73

    Article  CAS  PubMed  Google Scholar 

  60. Monteleone I, Sarra M, Blanco GD, Paoluzi OA, Franzè E, Fina D, Fabrizi A, MacDonald TT, Pallone F, Monteleone G (2010) Characterization of IL-17A–producing cells in celiac disease mucosa. J Immunol 184(4):2211–2218

    Article  CAS  PubMed  Google Scholar 

  61. Lahdenperä AI, Hölttä V, Ruohtula T, Salo HM, Orivuori L, Westerholm-Ormio M, Savilahti E, Fälth-Magnusson K, Högberg L, Ludvigsson J, Vaarala O (2012) Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes. Clin Exp Immunol 167(2):226–234

    Article  PubMed  PubMed Central  Google Scholar 

  62. Loo YM, Gale M Jr (2011) Immune signaling by RIG-I-like receptors. Immunity 34(5):680–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Abadie V, Kim SM, Lejeune T, Palanski BA, Ernest JD, Tastet O, Voisine J, Discepolo V, Marietta EV, Hawash MB, Ciszewski C (2020) IL-15, gluten and HLA-DQ8 drive tissue destruction in coeliac disease. Nature 578(7796):600–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Manavalan JS, Hernandez L, Shah JG, Konikkara J, Naiyer AJ, Lee AR, Ciaccio E, Minaya MT, Green PH, Bhagat G (2010) Serum cytokine elevations in celiac disease: association with disease presentation. Hum Immunol 71(1):50–57

    Article  CAS  PubMed  Google Scholar 

  65. Bayardo M, Punzi F, Bondar C, Chopita N, Chirdo F (2012) Transglutaminase 2 expression is enhanced synergistically by interferon-γ and tumour necrosis factor-α in human small intestine. Clin Exp Immunol 168(1):95–104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Corridoni D, Arseneau KO, Cifone MG, Cominelli F (2014) The dual role of nod-like receptors in mucosal innate immunity and chronic intestinal inflammation. Front Immunol 10(5):317

    Google Scholar 

  67. Palová-Jelínková L, Dáňová K, Drašarová H, Dvořák M, Funda DP, Fundová P, Kotrbová-Kozak A, Černá M, Kamanová J, Martin SF, Freudenberg M, Tučková L (2013) Pepsin digest of wheat gliadin fraction increases production of IL-1β via TLR4/MyD88/TRIF/MAPK/NF-κB signaling pathway and an NLRP3 inflammasome activation. PLoS ONE 8(4):e62426

    Article  PubMed  PubMed Central  Google Scholar 

  68. Bao F, Green PH, Bhagat G (2012) An update on celiac disease histopathology and the road ahead. Arch Pathol Lab Med 136(7):735–745

    Article  PubMed  Google Scholar 

  69. Thomas KE, Sapone A, Fasano A, Vogel SN (2006) Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease. J Immunol 176(4):2512–2521

    Article  CAS  PubMed  Google Scholar 

  70. Ghasiyari H, Rostami-Nejad M, Amani D, Rostami K, Pourhoseingholi MA, Asadzadeh-Aghdaei H, Zali MR (2018) Diverse profiles of toll-like receptors 2, 4, 7, and 9 mRNA in peripheral blood and biopsy specimens of patients with celiac disease. J Immunol Res. https://doi.org/10.1155/2018/7587095

    Article  PubMed  PubMed Central  Google Scholar 

  71. Kalliomäki M, Satokari R, Lähteenoja H, Vähämiko S, Grönlund J, Routi T, Salminen S (2012) Expression of microbiota, toll-like receptors, and their regulators in the small intestinal mucosa in Celiac disease. J Pediatr Gastroenterol Nutr 54(6):727–732

    Article  PubMed  Google Scholar 

  72. Eiró N, González-Reyes S, González L, González LO, Altadill A, Andicoechea A, Fresno-Forcelledo MF, Rodrigo-Sáez L, Vizoso FJ (2012) Duodenal expression of toll-like receptors and interleukins are increased in both children and adult celiac patients. Dig Dis Sci 57(9):2278–2285

    Article  PubMed  Google Scholar 

  73. Wertz IE (2014) TNFR1-activated NF-κB signal transduction: regulation by the ubiquitin/proteasome system. Curr Opin Chem Biol 1(23):71–77

    Article  Google Scholar 

  74. Shalimar DM, Das P, Sreenivas V, Gupta SD, Panda SK, Makharia GK (2013) Mechanism of villous atrophy in celiac disease: role of apoptosis and epithelial regeneration. Arch Pathol Lab Med 137(9):1262–1269

    Article  CAS  PubMed  Google Scholar 

  75. Green PH, Lebwohl B, Greywoode R (2015) Celiac disease. J Allergy Clin Immunol 135(5):1099–1106

    Article  CAS  PubMed  Google Scholar 

  76. Di Sabatino A, Rovedatti L, Rosado MM, Carsetti R, Corazza GR, MacDonald TT (2009) Increased expression of mucosal addressin cell adhesion molecule 1 in the duodenum of patients with active celiac disease is associated with depletion of integrin α4β7-positive T cells in blood. Hum Pathol 40(5):699–704

    Article  PubMed  Google Scholar 

  77. Li Y, He X, Schembri-King J, Jakes S, Hayashi J (2000) Cloning and characterization of human Lnk, an adaptor protein with pleckstrin homology and Src homology 2 domains that can inhibit T cell activation. J Immunol 164(10):5199–5206

    Article  CAS  PubMed  Google Scholar 

  78. Dale BL, Madhur MS (2016) Linking inflammation and hypertension via LNK/SH2B3. Curr Opin Nephrol Hypertens 25(2):87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Düwel M, Welteke V, Oeckinghaus A, Baens M, Kloo B, Ferch U, Darnay BG, Ruland J, Marynen P, Krappmann D (2009) A20 negatively regulates T cell receptor signaling to NF-κB by cleaving Malt1 ubiquitin chains. J Immunol 182(12):7718–7728

    Article  PubMed  Google Scholar 

  80. Sun Z, Arendt CW, Ellmeier W, Schaeffer EM, Sunshine MJ, Gandhi L, Annes J, Petrzilka D, Kupfer A, Schwartzberg PL, Littman DR (2000) PKC-θ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 404(6776):402–407

    Article  CAS  PubMed  Google Scholar 

  81. Rawlings DJ, Sommer K, Moreno-García ME (2006) The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes. Nat Rev Immunol 6(11):799–812

    Article  CAS  PubMed  Google Scholar 

  82. Hayden MS, Ghosh S (2008) Shared principles in NF-κB signaling. Cell 132(3):344–362

    Article  CAS  PubMed  Google Scholar 

  83. Hayden MS, Ghosh S (2014) Regulation of NF-κB by TNF family cytokines. Semin Immunol 26(3):253–266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Rosebeck S, Rehman AO, Lucas PC, McAllister-Lucas LM (2011) From MALT lymphoma to the CBM signalosome: three decades of discovery. Cell Cycle 10(15):2485–2496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Rebeaud F, Hailfinger S, Posevitz-Fejfar A, Tapernoux M, Moser R, Rueda D, Gaide O, Guzzardi M, Iancu EM, Rufer N, Fasel N (2008) The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat Immunol 9(3):272–281

    Article  CAS  PubMed  Google Scholar 

  86. Trynka G, Zhernakova A, Romanos J, Franke L, Hunt KA, Turner G, Bruinenberg M, Heap GA, Platteel M, Ryan AW, De Kovel C (2009) Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-κBsignalling. Gut 58(8):1078–1083

    Article  CAS  PubMed  Google Scholar 

  87. Leonard WJ, Spolski R (2005) Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat Rev Immunol 5(9):688–698

    Article  CAS  PubMed  Google Scholar 

  88. Skvortsova K, Stirzaker C, Taberlay P (2019) The DNA methylation landscape in cancer. Essays Biochem 63(6):797–811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Klutstein M, Nejman D, Greenfield R, Cedar H (2016) DNA methylation in cancer and aging. Can Res 76(12):3446–3450

    Article  CAS  Google Scholar 

  90. Bansal A, Pinney SE (2017) DNA methylation and its role in the pathogenesis of diabetes. Pediatr Diabetes 18(3):167–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Küçükali CI, Kürtüncü M, Coban A, Cebi M, Tüzün E (2015) Epigenetics of multiple sclerosis: an updated review. Neuromol med 17(2):83–96

    Article  Google Scholar 

  92. Mohn F, Weber M, Rebhan M, Roloff TC, Richter J, Stadler MB, Bibel M, Schübeler D (2008) Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol Cell 30(6):755–766

    Article  CAS  PubMed  Google Scholar 

  93. Comb M, Goodman HM (1990) CpG methylation inhibits proenkephalin gene expression and binding of the transcription factor AP-2. Nucleic Acids Res 18(13):3975–3982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31(2):89–97

    Article  CAS  PubMed  Google Scholar 

  95. Hutchinson JN, Raj T, Fagerness J, Stahl E, Viloria FT, Gimelbrant A, Seddon J, Daly M, Chess A, Plenge R (2014) Allele-specific methylation occurs at genetic variants associated with complex disease. PLoS ONE. https://doi.org/10.1371/journal.pone.0098464

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

SS, PK and SG acknowledged the support from DST FIST (Grant No. SR/FST/LS-1/2017/49-C) Funded Department of Human Genetics and Molecular Medicine at Central University of Punjab.

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Authors and Affiliations

  1. Immunogenomics Laboratory, Department of Human Genetics & Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, 151401, India

    Souparni Ghosh & Sabyasachi Senapati

  2. Laboratory for Reproductive and Developmental Disorders, Department of Human Genetics & Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India

    Preeti Khetarpal

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  1. Souparni Ghosh
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  2. Preeti Khetarpal
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  3. Sabyasachi Senapati
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Contributions

SS and SG: Conceptualized and wrote the manuscript and reviewed before submission for publication. SG: Prepared the figures. PK: Critically reviewed and gave inputs in writing the manuscript.

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Correspondence to Sabyasachi Senapati.

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Ghosh, S., Khetarpal, P. & Senapati, S. Functional implications of the CpG island methylation in the pathogenesis of celiac disease. Mol Biol Rep 49, 10051–10064 (2022). https://doi.org/10.1007/s11033-022-07585-w

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  • DOI: https://doi.org/10.1007/s11033-022-07585-w

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