Potential link between Fusobacterium enrichment and DNA methylation accumulation in the inflammatory colonic mucosa in ulcerative colitis
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Tomomitsu Tahara1, Ichiro Hirata2, Naoko Nakano1, Sayumi Tahara3, Noriyuki Horiguchi1, Tomohiko Kawamura1, Masaaki Okubo1, Takamitsu Ishizuka1, Hyuga Yamada1, Dai Yoshida1, Takafumi Ohmori1, Kohei Maeda1, Naruomi Komura1, Hirokazu Ikuno1, Yasutaka Jodai1, Toshiaki Kamano1, Mitsuo Nagasaka1, Yoshihito Nakagawa1, Tetsuya Tuskamoto3, Makoto Urano3, Tomoyuki Shibata1, Makoto Kuroda3 and Naoki Ohmiya1
1Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan
2Department of Gastroenterology, Kenporen Osaka Central Hospital Japan, Osaka, Japan
3Department of Diagnostic Pathology I, School of Medicine, Fujita Health University, Toyoake, Japan
Tomomitsu Tahara, email: [email protected]
Keywords: DNA methylation, colonic mucosa, ulcerative colitis, Fusobacterium, genome-wide methylation
Received: February 08, 2017 Accepted: May 23, 2017 Published: June 27, 2017
BACKGROUND AND AIM: Fusobacterium enrichment has been associated with colorectal cancer development. Ulcerative colitis (UC) associated tumorigenesis is characterized as high degree of methylation accumulation through continuous colonic inflammation. The aim of this study was to investigate a potential link between Fusobacterium enrichment and DNA methylation accumulation in the inflammatory colonic mucosa in UC.
METHODS: In the candidate analysis, inflamed colonic mucosa from 86 UC patients were characterized the methylation status of colorectal a panel of cancer related 24 genes. In the genome-wide analysis, an Infinium HumanMethylation450 BeadChip array was utilized to characterize the methylation status of >450,000 CpG sites for fourteen UC patients. Results were correlated with Fusobacterium status.
RESULTS: UC with Fusobacterium enrichment (FB-high) was characterized as high degree of type C (for cancer-specific) methylation compared to other (FB-low/neg) samples (P<0.01). Genes hypermethylated in FB-high samples included well-known type C genes in colorectal cancer, such as MINT2 and 31, P16 and NEUROG1. Multivariate analysis demonstrated that the FB high status held an increased likelihood for methylation high as an independent factor (odds ratio: 16.18, 95% confidence interval: 1.94-135.2, P=0.01). Genome-wide methylation analysis demonstrated a unique methylome signature of FB-high cases irrespective of promoter, outside promoter, CpG and non-CpG sites. Group of promoter CpG sites that were exclusively hypermethylated in FB-high cases significantly codified the genes related to the catalytic activity (P=0.039).
CONCLUSION: Our findings suggest that Fusobacterium accelerates DNA methylation in specific groups of genes in the inflammatory colonic mucosa in UC.
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