Genome imprinting mechanism based on the chromatin higher order structure

• Project/Area Number: 17K07248
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Genome biology
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Tomikawa Junko 国立研究開発法人国立成育医療研究センター, 周産期病態研究部, 研究員 (80534990)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: アレル特異的ループ形成 / Grb10 / シスエレメント / アレル特異的ループ構造 / CTCF / アレル特異的 / SNPsplit / 片アレル型オープンクロマチン / 両アレル型オープンクロマチン / ゲノム / 発現制御

Outline of Final Research Achievements

Using mouse ES cell line, we analyzed allele-specific epigenomic profile including gene expression, histone modification and chromatin loop conformation. Comparative analysis of genome-wide chromatin loop formation showed that no marked differentiations were observed between maternal and paternal alleles. However, the locus of already-known imprinting gene, Grb10, showed maternal-specific expression and maternal-specific loop formation between the major promoter and a region in which H3K27ac and H3K4me1 modifications were found. We then made the knockout mice lacking the region with H3K27ac and H3K4me1 modifications and investigated the phenotypes of the knockout mice.

Academic Significance and Societal Importance of the Research Achievements

ゲノムインプリンティングは哺乳動物の発生や発育に重要な働きをしており、そのエピジェネティック制御機構の破綻はヒトでは先天異常や癌の発生に関与することが知られている。また、インプリント遺伝子はありふれた（罹患率の高い）疾患にも関与することが示唆されている。例えば、近年の全ゲノム関連解析で、複数の糖尿病感受性SNPがインプリント遺伝子クラスター内に同定されている。マウス細胞をモデル系としてインプリント遺伝子発現に関与するシスエレメントを同定することで、このような疾患感受性SNPの機能推定が可能となると期待される。

Research Products

• [Journal Article] Epitranscriptomic profiling in human placenta: N6‐methyladenosine modification at the 5′‐untranslated region is related to fetal growth and preeclampsia (2020)
  • Author(s): Taniguchi Kosuke、Kawai Tomoko、Kitawaki Jo、Tomikawa Junko、Nakabayashi Kazuhiko、Okamura Kohji、Sago Haruhiko、Hata Kenichiro
  • Journal Title: The FASEB Journal Volume: 34 Issue: 1 Pages: 494-512
  • DOI: 10.1096/fj.201900619rr
  • Peer Reviewed / Open Access
• [Journal Article] Conditional Kisspeptin Neuron-Specific Kiss1 Knockout With Newly Generated Kiss1-floxed and Kiss1-Cre Mice Replicates a Hypogonadal Phenotype of Global Kiss1 Knockout Mice (2020)
  • Author(s): Kana Ikegami, Teppei Goto, Sho Nakamura, Youki Watanabe, Arisa Sugimoto, Sutisa Majarune, Kei Horihata, Mayuko Nagae, Junko Tomikawa, Takuya Imamura, Makoto Sanbo, Masumi Hirabayashi, Naoko Inoue, Kei-Ichiro Maeda, Hiroko Tsukamura, Yoshihisa Uenoyama
  • Journal Title: J Reprod Dev. Volume: in press Issue: 4 Pages: 359-367
  • DOI: 10.1262/jrd.2020-026
  • NAID: 130007888736
  • Peer Reviewed / Open Access
• [Journal Article] Inducible Kiss1 knockdown in the hypothalamic arcuate nucleus suppressed pulsatile secretion of luteinizing hormone in male mice (2020)
  • Author(s): Shiori Minabe, Sho Nakamura, Eri Fukushima, Marimo Sato, Kana Ikegami, Teppei Goto, Makoto Sanbo, Masumi Hirabayashi, Junko Tomikawa, Takuya Imamura, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei-Ichiro Maeda, Fuko Matsuda
  • Journal Title: Journal of Reproduction and Development Volume: Epub Issue: 4 Pages: 369-375
  • DOI: 10.1262/jrd.2019-164
  • NAID: 130007888724
  • Peer Reviewed / Open Access
• [Journal Article] Exploring trophoblast-specific Tead4 enhancers through chromatin conformation capture assays followed by functional screening (2019)
  • Author(s): Tomikawa Junko、Takada Shuji、Okamura Kohji、Terao Miho、Ogata-Kawata Hiroko、Akutsu Hidenori、Tanaka Satoshi、Hata Kenichiro、Nakabayashi Kazuhiko
  • Journal Title: Nucleic Acids Research Volume: 48 Issue: 1 Pages: 278-289
  • DOI: 10.1093/nar/gkz1034
  • Peer Reviewed / Open Access
• [Journal Article] CTCF deletion syndrome: Clinical features and epigenetic delineation (2017)
  • Author(s): Hori I, Kawamura R, Nakabayashi K, Watanabe H, Higashimoto K, Tomikawa J, Ieda D, Ohashi K, Negishi Y, Hattori A, Sugio Y, Wakui K, Hata K, Soejima H, Kurosawa K, Saitoh S
  • Journal Title: Journal of Medical Genetics Volume: 54 Issue: 12 Pages: 836-842
  • DOI: 10.1136/jmedgenet-2017-104854
  • Peer Reviewed / Open Access
• [Presentation] 染色体間相互作用を介した細胞系列特異的Tead4発現制御 (2019)
  • Author(s): 冨川順子、高田修治、岡村浩司、阿久津英憲、田中智、秦健一郎、中林一彦
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] 発生段階特異的な機能的ゲノム高次構造の探索 (2018)
  • Author(s): 冨川順子、西園啓文、秦健一郎、中林一彦
  • Organizer: 第12回日本エピジェネティクス研究会年会
• [Presentation] Tead4 interactome organized for mouse extraembryonic cell lineage specification (2017)
  • Author(s): Junko Tomikawa, Shuji Takada, Kohji Okamura, Keiko Hayashi, Miho Terao, Hidenori Akutsu, Satoshi Tanaka, Kenichiro Hata, Kazuhiko Nakabayashi
  • Organizer: 72nd Fujihara Seminar
• [Presentation] 染色体間相互作用を介した細胞系列特異的Tead4発現制御 (2017)
  • Author(s): 冨川順子、高田修治、岡村浩司、阿久津英憲、田中智、秦健一郎、中林一彦
  • Organizer: 第35回染色体ワークショップ・第16回核ダイナミクス研究会