title: Tissue-specific demethylation in CpG-poor promoters during cellular differentiation.
abstract: Epigenetic regulation is essential in determining cellular phenotypes during differentiation. Although tissue-specific DNA methylation has been studied, the significance of methylation variance for tissue phenotypes remains unresolved, especially for CpG-poor promoters. Here, we comprehensively studied methylation levels of 27 578 CpG sites among 21 human normal tissues from 12 anatomically different regions using an epigenotyping beadarray system. Remarkable changes in tissue-specific DNA methylation were observed within CpG-poor promoters but not CpG-rich promoters. Of note, tissue-specific hypomethylation is accompanied by an increase in gene expression, which gives rise to specialized cellular functions. The hypomethylated regions were significantly enriched with recognition motifs for transcription factors that regulate cell-type-specific differentiation. To investigate the dynamics of hypomethylation events, we analyzed methylation levels of the entire APOA1 gene locus during in vitro differentiation of embryonic stem cells toward the hepatic lineage. A decrease in methylation was observed after day 13, coinciding with alpha-fetoprotein detection, in the vicinity of its transcription start sites (TSSs), and extends up to ∼200 bp region encompassing the TSS at day 21, equivalent to the hepatoblastic stage. This decrease is even more pronounced in the adult liver, where the entire APOA1 gene locus is hypomethylated. Furthermore, when we compared the methylation status of induced pluripotent stem (iPS) cells with their parental cell, IMR-90, we found that fibroblast-specific hypomethylation is restored to a fully methylated state in iPS cells after reprogramming. These results illuminate tissue-specific methylation dynamics in CpG-poor promoters and provide more comprehensive views on spatiotemporal gene regulation in terminal differentiation.
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology and Department of Pathology, University of Tokyo, Tokyo, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Nagae
authors.forename: Takayuki
authors.initials: T
authors.lastname: Isagawa
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Shiraki
authors.forename: Takanori
authors.initials: T
authors.lastname: Fujita
authors.forename: Shogo
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Aya
authors.initials: A
authors.lastname: Nonaka
authors.forename: Sayaka
authors.initials: S
authors.lastname: Yoshiba
authors.forename: Keisuke
authors.initials: K
authors.lastname: Matsusaka
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Midorikawa
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Soejima
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Suemori
authors.forename: Norio
authors.initials: N
authors.lastname: Nakatsuji
authors.forename: Shoen
authors.initials: S
authors.lastname: Kume
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000502:physiology*; D018899:CpG Islands / Q000502:physiology*; D019175:DNA Methylation / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009928:Organ Specificity / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology*