title: Epigenetic control of the host gene by commensal bacteria in large intestinal epithelial cells.
abstract: Intestinal epithelial cells (IECs) are continuously exposed to large numbers of commensal bacteria but are relatively insensitive to them, thereby averting an excessive inflammatory reaction. We have previously reported that the hyporesponsiveness of a human IEC line to LPS was primarily the result of a down-regulation of TLR4 gene transcription through epigenetic mechanisms. In the present study we show that DNA methylation in the 5' region of the TLR4 gene is significantly higher in IECs than in splenic cells in vivo. The methylation was shown to be dependent on the differentiation state of the IECs, as the differentiated IEC population that expressed higher levels of intestinal alkaline phosphatase (IAP) also displayed greater methylation and lower expression of the TLR4 gene than the undifferentiated population. The IAP(high), differentiated population also showed less abundant expression of CDX2, the transcription factor required for the development of the intestine, than the IAP(low), undifferentiated population. Overexpression of CDX2 in an IEC line decreased the methylation level of the TLR4 gene, increased transcriptional promoter activity of the gene, and increased responsiveness to the TLR4 ligand. Furthermore, the methylation level of the TLR4 gene was significantly lower in IECs of the large intestine of germ-free mice than in those of conventional mice, whereas the level in IECs of the small intestine was almost equal between these mice, indicating that commensal bacteria contribute to the maintenance of intestinal symbiosis by controlling epigenetic modification of the host gene in the large intestine.
authors.affiliation: Food and Physiological Functions Laboratory, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880, Japan. Electronic address: ktaka@brs.nihon-u.ac.jp.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Food and Physiological Functions Laboratory, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sugi
authors.affiliation: Food and Physiological Functions Laboratory, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880, Japan.
authors.forename: Kou
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Food and Physiological Functions Laboratory, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Food and Physiological Functions Laboratory, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Kurihara
authors.affiliation: Food and Physiological Functions Laboratory, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hosono
authors.affiliation: Food and Physiological Functions Laboratory, College of Bioresource Sciences, Nihon University, 1866 Kameino, Fujisawa-shi, Kanagawa 252-0880, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaminogawa
mesh_terms: D000818:Animals; D001419:Bacteria / Q000254:growth & development / Q000378:metabolism*; D000071616:CDX2 Transcription Factor; D018938:Caco-2 Cells; D019175:DNA Methylation / Q000502:physiology; D044127:Epigenesis, Genetic / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology; D005856:Germ-Free Life / Q000502:physiology*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007420:Intestine, Large / Q000378:metabolism* / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014157:Transcription Factors