Epigenomic regulation in congenital anomaly syndromes

• Project/Area Number: 26670490
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: Aoki Yoko 東北大学, 医学(系)研究科(研究院), 教授 (80332500)
• Co-Investigator(Kenkyū-buntansha): MATSUBARA Yoichi 国立研究開発法人国立成育医療研究センター, 研究所, 所長 (00209602) ; NIIHORI Tetsuya 東北大学, 大学院医学系研究科, 准教授 (40436134) ; INOUE Shinichi 東北大学, 大学院医学系研究科, 助教 (70622091)
• Research Collaborator: YAOITA Masako 東北大学, 大学院医学系研究科 ; OBA Daiju 東北大学, 大学院医学系研究科 ; NISHIYAMA Ayumi 東北大学, 大学院医学系研究科 ; UMEKI Ikumi 東北大学, 大学院医学系研究科 ; TAKAHARA Shingo 東北大学, 大学院医学系研究科
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ヌーナン症候群 / RAS / エピゲノム / RAS/MAPシグナル伝達経路 / RAS/MAPK / BRAF

Outline of Final Research Achievements

In this study, we analyzed genes that are associated with epigenetic modifications in patients, who are clinically diagnosed as having RASopathies, and identified pathogenic mutations in three affected individuals. We generated a knock-in mice expressing a Braf p.Q241R mutation, as a model mice for CFC syndrome. Treatment with a MEK inhibitor, PD0325901, and a histone H3K27 demethylase inhibitor, GSK-J4, have rescued embryonic lethality in BrafQ241R/+ mice. To explore the mechanisms of efficacy in PD0325901 and GSK-J4 co-treatment, we examined mRNA and protein levels of histone H3K27 methylase and histone H3K27 demethylases in heart tissues from control and BrafQ241R/+ embryos. Further analysis on methylation profiling of H3K27 in each gene will clarify the mechanisms why co-treatment of PD0325901 and GSK-J4 rescued the embryonic lethality in in BrafQ241R/+ mice.

Research Products

• [Journal Article] Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations. (2016)
  • Author(s): Yaoita M, Niihori T, Mizuno S, Okamoto N, Hayashi S, Watanabe A, Yokozawa M, Suzumura H, Nakahara A, Nakano Y, Hokosaki T, Ohmori A, Sawada H, Migita O, Mima A, Lapunzina P, Santos-Simarro F, García-Miñaúr S, Ogata T, Kawame H, Kurosawa K, Ohashi H, Inoue S, Matsubara Y, Kure S, Aoki Y.
  • Journal Title: Hum Genet. Volume: 135 Issue: 2 Pages: 209-222
  • DOI: 10.1007/s00439-015-1627-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous syndrome phenotype. (2015)
  • Author(s): Moriya M, Inoue S, Miyagawa-Tomita S, Nakashima Y, Oba D, Niihori T, Hashi M, Ohnishi H, Kure S, Matsubara Y, Aoki Y.
  • Journal Title: Hum Mol Genet. Volume: 24 Issue: 25 Pages: 7349-7360
  • DOI: 10.1093/hmg/ddv435
  • Peer Reviewed
• [Journal Article] Somatic BRAF c.1799T>A p.V600E Mosaicism syndrome characterized by a linear syringocystadenoma papilliferum, anaplastic astrocytoma, and ocular abnormalities. (2015)
  • Author(s): Watanabe Y, Shido K, Niihori T, Niizuma H, Katata Y, Iizuka C, Oba D, Moriya K, Saito-Nanjo Y, Onuma M, Rikiishi T, Sasahara Y, Watanabe M, Aiba S, Saito R, Sonoda Y, Tominaga T, Aoki Y, Kure S.
  • Journal Title: Am J Med Genet A. Volume: 170 Issue: 1 Pages: 189-194
  • DOI: 10.1002/ajmg.a.37376
  • Peer Reviewed
• [Journal Article] New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome. (2014)
  • Author(s): Inoue S. I. et al.
  • Journal Title: Hum. Mol. Genet. Volume: 23 Issue: 24 Pages: 6553-6566
  • DOI: 10.1093/hmg/ddu376
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Bilateral giant coronary aneurysms in a 40-year-old male with Noonan syndrome caused by a KRAS germline mutation. (2014)
  • Author(s): Fujimoto N, Nakajima H, Sugiura E, Dohi K, Kanemitsu S, Yamada N, Aoki Y, Nakatani K, Shimpo H, Nobori T, Ito M
  • Journal Title: Int J Cadiol Volume: 173 Issue: 3 Pages: e63-e66
  • DOI: 10.1016/j.ijcard.2014.03.135
  • Peer Reviewed / Open Access
• [Presentation] RASopathiesの最近の進歩 (2015)
  • Author(s): 青木洋子
  • Organizer: 第7回日本レックリングハウゼン病学会学術大会
  • Place of Presentation: 東京（慶應義塾大学）
  • Year and Date: 2015-11-29
  • Invited
• [Presentation] Cardio-facio-cutaneous症候群モデルマウスを用いた治療法研究 (2015)
  • Author(s): 井上晋一、守谷充司、渡邉裕介、宮川－富田幸子、新堀哲也、大場大樹、小野栄夫、呉繁夫、小椋利彦、松原洋一、青木洋子
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 東京（京王プラザホテル）
  • Year and Date: 2015-10-14
• [Presentation] Cardio-facio-cutaneous症候群のモデルマウス作製とその病態解析 (2015)
  • Author(s): 青木洋子、井上晋一、守谷充司、大場大樹、新堀哲也、呉繁夫、松原洋一
  • Organizer: 第118回日本小児科学会学術集会
  • Place of Presentation: 大阪（大阪国際会議場 / リーガロイヤルホテル大阪）
  • Year and Date: 2015-04-17
• [Presentation] Molecular analysis of RASopathies using next generation sequencer (2014)
  • Author(s): Aoki Y, Niihori T, Inoue SI and Matsubara Y
  • Organizer: The 14 th East Asian Union of Human Genetics (EAUHGS) Annual Meeting.
  • Place of Presentation: 東京、タワーホール船橋
  • Year and Date: 2014-11-20
  • Invited
• [Presentation] 新規BRAFノックインマウスの作製によるcardio-facio-cutaneous症候群の病態解明と治療法研究 (2014)
  • Author(s): 井上晋一、守谷充司、渡邉裕介、宮川－富田幸子、新堀哲也、大場大樹、小野栄夫、呉繁夫、小椋利彦、松原洋一、青木洋子
  • Organizer: 第59回日本人類遺伝学会
  • Place of Presentation: 東京、タワーホール船橋
  • Year and Date: 2014-11-19 – 2014-11-22
• [Presentation] ヌーナン症候群の新規原因遺伝子RIT1の同定 (2014)
  • Author(s): 青木洋子、新堀哲也、岡本伸彦、水野誠司、黒澤健司、緒方勤、井上晋一、松原洋一
  • Organizer: 第117回日本小児科学会学術集会
  • Place of Presentation: 名古屋、名古屋国際会議場
  • Year and Date: 2014-04-11 – 2014-04-13
• [Remarks] 東北大学 大学院医学系研究科 遺伝医療学分野
  • URL: http://www.medgen.med.tohoku.ac.jp/
• [Remarks] 東北大学 大学院医学系研究科 遺伝病学分野
  • URL: http://www.medgen.med.tohoku.ac.jp/