DNA methylation status of Epithelial-Mesenchymal Transition (EMT) - Related genes is associated with severe clinical phenotypes in Ulcerative Colitis (UC)

Tomomitsu Tahara, Tomoyuki Shibata, Masaaki Okubo, Takamitsu Ishizuka, Masakatsu Nakamura, Mitsuo Nagasaka, Yoshihito Nakagawa, Naoki Omiya, Tomiyasu Arisawa, Ichiro Hirata

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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 noninflammatory 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.

Original languageEnglish
JournalPLoS One
Volume9
Issue number10
DOIs
Publication statusPublished - 10-10-2014

Fingerprint

Epithelial-Mesenchymal Transition
colitis
DNA methylation
DNA Methylation
Ulcerative Colitis
Genes
Methylation
Phenotype
phenotype
mucosa
Mucous Membrane
methylation
genes
Refractory materials
promoter regions
CpG Islands
Biopsy
Surgery
bisulfites
Steroids

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Tahara, Tomomitsu ; Shibata, Tomoyuki ; Okubo, Masaaki ; Ishizuka, Takamitsu ; Nakamura, Masakatsu ; Nagasaka, Mitsuo ; Nakagawa, Yoshihito ; Omiya, Naoki ; Arisawa, Tomiyasu ; Hirata, Ichiro. / DNA methylation status of Epithelial-Mesenchymal Transition (EMT) - Related genes is associated with severe clinical phenotypes in Ulcerative Colitis (UC). In: PLoS One. 2014 ; Vol. 9, No. 10.
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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 noninflammatory 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.",
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DNA methylation status of Epithelial-Mesenchymal Transition (EMT) - Related genes is associated with severe clinical phenotypes in Ulcerative Colitis (UC). / Tahara, Tomomitsu; Shibata, Tomoyuki; Okubo, Masaaki; Ishizuka, Takamitsu; Nakamura, Masakatsu; Nagasaka, Mitsuo; Nakagawa, Yoshihito; Omiya, Naoki; Arisawa, Tomiyasu; Hirata, Ichiro.

In: PLoS One, Vol. 9, No. 10, 10.10.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - DNA methylation status of Epithelial-Mesenchymal Transition (EMT) - Related genes is associated with severe clinical phenotypes in Ulcerative Colitis (UC)

AU - Tahara, Tomomitsu

AU - Shibata, Tomoyuki

AU - Okubo, Masaaki

AU - Ishizuka, Takamitsu

AU - Nakamura, Masakatsu

AU - Nagasaka, Mitsuo

AU - Nakagawa, Yoshihito

AU - Omiya, Naoki

AU - Arisawa, Tomiyasu

AU - Hirata, Ichiro

PY - 2014/10/10

Y1 - 2014/10/10

N2 - 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 noninflammatory 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.

AB - 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 noninflammatory 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.

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