title: DNA methylation status of epithelial-mesenchymal transition (EMT)--related genes is associated with severe clinical phenotypes in ulcerative colitis (UC).
abstract: BACKGROUND
  Epithelial-to-mesenchymal transition (EMT) is a phenomenon that allows the conversion of adherent epithelial cells to a mesenchymal cell phenotype, which enhances migratory capacity and invasiveness. Recent studies have suggested that EMT contributes to the pathogenesis of ulcerative colitis (UC). We investigated the promoter DNA methylation status of EMT-related genes in the colonic mucosa in UC.
  
  
  METHODS
  Colonic biopsies were obtained from the rectal inflammatory mucosa of 86 UC patients and the non-inflammatory proximal colonic mucosa of 10 paired patients. Bisulfite pyrosequencing was used to quantify the methylation of 5 candidate CpG island promoters (NEUROG1, CDX1, miR-1247, CDH1, and CDH13) and LINE1.
  
  
  RESULTS
  Using an unsupervised hierarchical clustering analysis, inflamed rectal mucosa was well separated from mucosa that appeared normal. The CDH1 and CDH13 promoters were significantly associated with patient age (p = 0.04, 0.03, respectively). A similar trend was found between those genes and the duration of disease (CDH1: p = 0.07, CDH13: p = 0.0002, mean of both: p<0.00001). Several positive associations were found between hypermethylation and severe clinical phenotypes (CDX1 and miR-1247 and a refractory phenotype: p = 0.04 and 0.006, respectively. miR-1247 and CDH1 hyper methylation and a more severe Mayo endoscopic subscore: miR-1247: p = 0.0008, CDH1: p = 0.03, mean of both: p = 0.003). When the severe clinical phenotype was defined as having any of five phenotypes (hospitalized more than twice, highest Mayo endoscopic subscore, steroid dependence, refractory, or a history of surgery) miR-1247 hypermethylation was associated with the same phenotype (p = 0.008).
  
  
  CONCLUSIONS
  Our data suggest that variability in the methylation status of EMT-related genes is associated with more severe clinical phenotypes in UC.
authors.affiliation: Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Tahara
authors.affiliation: Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Okubo
authors.affiliation: Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Ishizuka
authors.affiliation: Department of Gastroenterology, Kanazawa Medical University, Ishikawa, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Nagasaka
authors.affiliation: Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ohmiya
authors.affiliation: Department of Gastroenterology, Kanazawa Medical University, Ishikawa, Japan.
authors.forename: Tomiyasu
authors.initials: T
authors.lastname: Arisawa
authors.affiliation: Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hirata
mesh_terms: D000328:Adult; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000473:pathology*; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D018899:CpG Islands; D019175:DNA Methylation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008297:Male