title: DNA methylation profile of Aire-deficient mouse medullary thymic epithelial cells.
abstract: BACKGROUND
  Medullary thymic epithelial cells (mTECs) are characterized by ectopic expression of self-antigens during the establishment of central tolerance. The autoimmune regulator (Aire), which is specifically expressed in mTECs, is responsible for the expression of a large repertoire of tissue-restricted antigens (TRAs) and plays a role in the development of mTECs. However, Aire-deficient mTECs still express TRAs. Moreover, a subset of mTECs, which are considered to be at a stage of terminal differentiation, exists in the Aire-deficient thymus. The phenotype of a specific cell type in a multicellular organism is governed by the epigenetic regulation system. DNA methylation modification is an important component of this system. Every cell or tissue type displays a DNA methylation profile, consisting of tissue-dependent and differentially methylated regions (T-DMRs), and this profile is involved in cell-type-specific genome usage. The aim of this study was to examine the DNA methylation profile of mTECs by using Aire-deficient mTECs as a model.
  
  
  RESULTS
  We identified the T-DMRs of mTECs (mTEC-T-DMRs) via genome-wide DNA methylation analysis of Aire(-/-) mTECs by comparison with the liver, brain, thymus, and embryonic stem cells. The hypomethylated mTEC-T-DMRs in Aire(-/-) mTECs were associated with mTEC-specific genes, including Aire, CD80, and Trp63, as well as other genes involved in the RANK signaling pathway. While these mTEC-T-DMRs were also hypomethylated in Aire(+/+) mTECs, they were hypermethylated in control thymic stromal cells. We compared the pattern of DNA methylation levels at a total of 55 mTEC-T-DMRs and adjacent regions and found that the DNA methylation status was similar for Aire(+/+) and Aire(-/-) mTECs but distinct from that of athymic cells and tissues.
  
  
  CONCLUSIONS
  These results indicate a unique DNA methylation profile that is independent of Aire in mTECs. This profile is distinct from other cell types in the thymic microenvironment and is indicated to be involved in the differentiation of the mTEC lineage.
authors.affiliation: Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences/Veterinary Medical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Guoying
authors.initials: G
authors.lastname: Wu
authors.forename: Keiji
authors.initials: K
authors.lastname: Hirabayashi
authors.forename: Shinya
authors.initials: S
authors.lastname: Sato
authors.forename: Nobuko
authors.initials: N
authors.lastname: Akiyama
authors.forename: Taishin
authors.initials: T
authors.lastname: Akiyama
authors.forename: Kunio
authors.initials: K
authors.lastname: Shiota
authors.forename: Shintaro
authors.initials: S
authors.lastname: Yagi
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002469:Cell Separation; D019175:DNA Methylation / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity / Q000235:genetics; D017154:Stromal Cells / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology*; D014157:Transcription Factors / Q000172:deficiency* / Q000378:metabolism; D024363:Transcription Initiation Site; D000096927:AIRE Protein
chemical_list: D015415:Biomarkers; D017493:Leukocyte Common Antigens; D014157:Transcription Factors; D000096927:AIRE Protein