Potential link between Fusobacterium enrichment and DNA methylation accumulation in the inflammatory colonic mucosa in ulcerative colitis

// Tomomitsu Tahara 1 , Ichiro Hirata 2 , Naoko Nakano 1 , Sayumi Tahara 3 , Noriyuki Horiguchi 1 , Tomohiko Kawamura 1 , Masaaki Okubo 1 , Takamitsu Ishizuka 1 , Hyuga Yamada 1 , Dai Yoshida 1 , Takafumi Ohmori 1 , Kohei Maeda 1 , Naruomi Komura 1 , Hirokazu Ikuno 1 , Yasutaka Jodai 1 , Toshiaki Kamano 1 , Mitsuo Nagasaka 1 , Yoshihito Nakagawa 1 , Tetsuya Tuskamoto 3 , Makoto Urano 3 , Tomoyuki Shibata 1 , Makoto Kuroda 3 and Naoki Ohmiya 1 1 Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan 2 Department of Gastroenterology, Kenporen Osaka Central Hospital Japan, Osaka, Japan 3 Department of Diagnostic Pathology I, School of Medicine, Fujita Health University, Toyoake, Japan Correspondence to: Tomomitsu Tahara, email: tomomiccyu@yahoo.co.jp Keywords: DNA methylation, colonic mucosa, ulcerative colitis, Fusobacterium , genome-wide methylation Received: February 08, 2017     Accepted: May 23, 2017     Published: June 27, 2017 ABSTRACT 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.