title: Novel sex-dependent differentially methylated regions are demethylated in adult male mouse livers.
abstract: In mammalian livers, sexual dimorphisms are observed in tissue-specific functions and diseases such as hepatocellular carcinoma. We identified sex-dependent differentially methylated regions (S-DMRs) which had been previously been characterized as growth hormone- STAT5 dependent. In this study, we performed genome-wide screening and identified ten additional hypomethylated S-DMR gene regions in male livers. Of these S-DMRs, Uggt2 and Sarnp were hypomethylated in both male and female livers compared to brain and embryonic stem (ES) cells. Similarly, Adam2, Uggt2, and Scp2 were hypomethylated in female embryonic germ (EG) cells and not in male EG cells, indicating that these S-DMRs are liver-specific male hypo-S-DMRs. Interestingly, the five S-DMRs were free from STAT5 chromatin immunoprecipitation (ChIP) signals, suggesting that S-DMRs are independent of the growth hormone-STAT5-pathway. Instead, the DNA methylation statuses of the S-DMRs of Adam2, Snx29, Uggt2, Sarnp, and Rnpc3 genes were under the control of testosterone. Importantly, the hypomethylated S-DMRs of the Adam2 and Snx29 regions showed chromatin decondensation. Epigenetic factors could be responsible for the sexual dimorphisms in DNA methylation status and chromatin structure, as the expression of Dnmt1, Dnmt3b, and Tet2 genes was lower in male mice compared to female mice and TET2 expression recovered following orchidectomy by testosterone treatment. In conclusion, we identified novel male-specific hypomethylated S-DMRs that contribute to chromatin decondensation in the liver. S-DMRs were tissue-specific and the hypomethylation is testosterone-dependent.
authors.affiliation: Department of Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Hirabayashi
authors.affiliation: Department of Microbiology, Division of Medicine, Interdisciplinary Graduate School of Medicine and Engineering (Faculty of Medicine), University of Yamanashi, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Moriishi
authors.affiliation: Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Matsui
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Moriya
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.affiliation: Department of Molecular Virology, Research Institute for Microbial Diseases Osaka University, Osaka, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Matsuura
authors.affiliation: Department of Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Tokyo, Japan. Electronic address: ashiota@mail.ecc.u-tokyo.ac.jp.
authors.forename: Kunio
authors.initials: K
authors.lastname: Shiota
authors.affiliation: Department of Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Tokyo, Japan. Electronic address: alfa155shin@me.com.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Yagi
mesh_terms: D000818:Animals; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D005234:Fatty Liver / Q000378:metabolism; D005260:Female; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012727:Sex Characteristics; D013739:Testosterone / Q000494:pharmacology
chemical_list: D002843:Chromatin; D013739:Testosterone
keywords: DNA methylation; S-DMRs; STAT5; Testosterone