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DNA methylation analysis of multiple imprinted DMRs in Sotos syndrome reveals IGF2-DMR0 as a DNA methylation-dependent, P0 promoter-specific enhancer.
Watanabe, Hidetaka; Higashimoto, Ken; Miyake, Noriko; Morita, Sumiyo; Horii, Takuro; Kimura, Mika; Suzuki, Takayuki; Maeda, Toshiyuki; Hidaka, Hidenori; Aoki, Saori; Yatsuki, Hitomi; Okamoto, Nobuhiko; Uemura, Tetsuji; Hatada, Izuho; Matsumoto, Naomichi; Soejima, Hidenobu.
Afiliación
  • Watanabe H; Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.
  • Higashimoto K; Department of Plastic and Reconstructive Surgery, Saga University Hospital, Saga, Japan.
  • Miyake N; Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.
  • Morita S; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • Horii T; Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
  • Kimura M; Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
  • Suzuki T; Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
  • Maeda T; Avian Bioscience Research Center, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan.
  • Hidaka H; Department of Pediatrics, Faculty of Medicine, Saga University, Saga, Japan.
  • Aoki S; Department of Internal Medicine and Gastrointestinal Endoscopy, Faculty of Medicine, Saga University, Saga, Japan.
  • Yatsuki H; Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.
  • Okamoto N; Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.
  • Uemura T; Department of Medical Genetics, Osaka Women's and Children's Hospital, Izumi, Japan.
  • Hatada I; Department of Plastic and Reconstructive Surgery, Saga University Hospital, Saga, Japan.
  • Matsumoto N; Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan.
  • Soejima H; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
FASEB J ; 34(1): 960-973, 2020 01.
Article en En | MEDLINE | ID: mdl-31914674
ABSTRACT
Haploinsufficiency of NSD1, which dimethylates histone H3 lysine 36 (H3K36), causes Sotos syndrome (SoS), an overgrowth syndrome. DNMT3A and DNMT3B recognizes H3K36 trimethylation (H3K36me3) through PWWP domain to exert de novo DNA methyltransferase activity and establish imprinted differentially methylated regions (DMRs). Since decrease of H3K36me3 and genome-wide DNA hypomethylation in SoS were observed, hypomethylation of imprinted DMRs in SoS was suggested. We explored DNA methylation status of 28 imprinted DMRs in 31 SoS patients with NSD1 defect and found that hypomethylation of IGF2-DMR0 and IG-DMR in a substantial proportion of SoS patients. Luciferase assay revealed that IGF2-DMR0 enhanced transcription from the IGF2 P0 promoter but not the P3 and P4 promoters. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) revealed active enhancer histone modifications at IGF2-DMR0, with high enrichment of H3K4me1 and H3 lysine 27 acetylation (H3K27ac). CRISPR-Cas9 epigenome editing revealed that specifically induced hypomethylation at IGF2-DMR0 increased transcription from the P0 promoter but not the P3 and P4 promoters. NSD1 knockdown suggested that NSD1 targeted IGF2-DMR0; however, IGF2-DMR0 DNA methylation and IGF2 expression were unaltered. This study could elucidate the function of IGF2-DMR0 as a DNA methylation dependent, P0 promoter-specific enhancer. NSD1 may play a role in the establishment or maintenance of IGF2-DMR0 methylation during the postimplantation period.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Factor II del Crecimiento Similar a la Insulina / N-Metiltransferasa de Histona-Lisina / Metilación de ADN / Síndrome de Sotos Límite: Child / Child, preschool / Female / Humans / Infant / Male / Newborn Idioma: En Año: 2020 Tipo del documento: Article
Texto completo
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XML
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Factor II del Crecimiento Similar a la Insulina / N-Metiltransferasa de Histona-Lisina / Metilación de ADN / Síndrome de Sotos Límite: Child / Child, preschool / Female / Humans / Infant / Male / Newborn Idioma: En Año: 2020 Tipo del documento: Article