title: Large hypomethylated domains serve as strong repressive machinery for key developmental genes in vertebrates.
abstract: DNA methylation is a fundamental epigenetic modification in vertebrate genomes and a small fraction of genomic regions is hypomethylated. Previous studies have implicated hypomethylated regions in gene regulation, but their functions in vertebrate development remain elusive. To address this issue, we generated epigenomic profiles that include base-resolution DNA methylomes and histone modification maps from both pluripotent cells and mature organs of medaka fish and compared the profiles with those of human ES cells. We found that a subset of hypomethylated domains harbor H3K27me3 (K27HMDs) and their size positively correlates with the accumulation of H3K27me3. Large K27HMDs are conserved between medaka and human pluripotent cells and predominantly contain promoters of developmental transcription factor genes. These key genes were found to be under strong transcriptional repression, when compared with other developmental genes with smaller K27HMDs. Furthermore, human-specific K27HMDs show an enrichment of neuronal activity-related genes, which suggests a distinct regulation of these genes in medaka and human. In mature organs, some of the large HMDs become shortened by elevated DNA methylation and associate with sustained gene expression. This study highlights the significance of domain size in epigenetic gene regulation. We propose that large K27HMDs play a crucial role in pluripotent cells by strictly repressing key developmental genes, whereas their shortening consolidates long-term gene expression in adult differentiated cells.
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tsukahara
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-0882, Japan.
authors.forename: Wei
authors.initials: W
authors.lastname: Qu
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-0882, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ichikawa
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Otsuka
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Ogoshi
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-0882, Japan.
authors.forename: Taro L
authors.initials: TL
authors.lastname: Saito
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.affiliation: Department of Medical Genome, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8561, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Sugano
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan Department of Laboratory Medicine, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-0882, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa 277-0882, Japan moris@cb.k.u-tokyo.ac.jp htakeda@biol.s.u-tokyo.ac.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Morishita
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan moris@cb.k.u-tokyo.ac.jp htakeda@biol.s.u-tokyo.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takeda
mesh_terms: D000818:Animals; D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D053595:Embryonic Stem Cells / Q000502:physiology*; D063185:Epigenetic Repression / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D008969:Molecular Sequence Data; D009990:Oryzias / Q000196:embryology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D017931:DNA Primers; D006657:Histones
keywords: DNA methylation; Epigenetics; H3K27me3; Large hypomethylated domain; Medaka; Vertebrate development