Study of the mechanism of nucleosome-enhanceosome conversion

• Project/Area Number: 18K19305
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
• Research Institution: Yokohama City University
• Principal Investigator: OGATA Kazuhiro 横浜市立大学, 医学研究科, 教授 (90260330)
• Co-Investigator(Kenkyū-buntansha): 仙石 徹 横浜市立大学, 医学部, 講師 (60576312) ; 浜田 恵輔 横浜市立大学, 医学部, 助教 (00344052)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 転写制御 / ヌクレオソーム / ヒストン修飾酵素 / クライオ電子顕微鏡 / 転写因子 / エンハンソソーム / 定量解析 / 転写制御機構

Outline of Final Research Achievements

Histone-modifying enzymes play an important role in the nucleosome-enhanceosome structural remodeling associated with transcriptional activation. In this study, we determined the three-dimensional structure of NSD2, a histone methyltransferase that dimethylated lysine 36 of histone H3 (H3K36), in complex with a nucleosome substrate by single-particle analysis using cryo-electron microscopy. In the absence of a nucleosome, NSD2 is inactive due to the binding of the autoinhibitory loop. However, in our structure, NSD2 bound to nucleosome coordinates the conformational change of the autoinhibitory loop and the dissociation of DNA from the nucleosome, resulting in the methylation of H3K36. In addition, the oncogenic variants of NSD2 destabilize the autoinhibitory loop, making the enzyme unable to maintain its inhibitory state.

Academic Significance and Societal Importance of the Research Achievements

分子構造レベルでのがん化の機構研究は、特に細胞質におけるシグナル伝達分子としてのリン酸化酵素やそのアロステリック制御因子であるGタンパク質の変異について解析が進んでおり、分子標的薬の開発のための基盤となっている。しかしながら転写因子やヒストン修飾酵素などの核内の分子の変異によるがん化については研究が遅れているのが現状である。本研究では、遺伝子発現に関与する分子複合体の構造解析により、がん化の引き金となる核内でのイベントを分子構造レベルで解明したことになり、核内因子を標的としたがん分子標的療法への道を開くことで、がん治療の適応範囲が大きく広がることが期待される。

Research Products

• [Journal Article] De novo ATP1A3 variants cause polymicrogyria (2021)
  • Author(s): Miyatake Satoko、Kato Mitsuhiro、Kumamoto Takuma、Hirose Tomonori、他
  • Journal Title: Science Advances Volume: 7 Issue: 13 Pages: 2368-2368
  • DOI: 10.1126/sciadv.abd2368
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] OTUD5 Variants Associated With X-Linked Intellectual Disability and Congenital Malformation (2021)
  • Author(s): Saida K, Fukuda T, Scott DA, Sengoku T, Ogata K, Nicosia A, Hernandez-Garcia A, Lalani SR, Azamian MS, Streff H, Liu P, Dai H, Mizuguchi T, Miyatake S, Asahina M, Ogata T, Miyake N, Matsumoto N.
  • Journal Title: Front Cell Dev Biol. Volume: 9 Pages: 631428-631428
  • DOI: 10.3389/fcell.2021.631428
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel PAK1 variant causative of neurodevelopmental disorder with postnatal macrocephaly (2020)
  • Author(s): Ohori Sachiko、Mitsuhashi Satomi、Ben-Haim Revital、Heyman Eli、Sengoku Toru、Ogata Kazuhiro、Matsumoto Naomichi
  • Journal Title: Journal of Human Genetics Volume: 65 Issue: 5 Pages: 481-485
  • DOI: 10.1038/s10038-020-0728-8
  • Peer Reviewed / Open Access
• [Journal Article] Phenotype?genotype correlations in patients with GNB1 gene variants, including the first three reported Japanese patients to exhibit spastic diplegia, dyskinetic quadriplegia, and infantile spasms (2020)
  • Author(s): Endo Wakaba, et al., Matsumoto Naomichi, Haginoya Kazuhiro
  • Journal Title: Brain and Development Volume: 42 Issue: 2 Pages: 199-204
  • DOI: 10.1016/j.braindev.2019.10.006
  • Peer Reviewed
• [Journal Article] Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities (2020)
  • Author(s): Miyake Noriko et al., Matsumoto Naomichi
  • Journal Title: The American Journal of Human Genetics Volume: 106 Issue: 1 Pages: 13-25
  • DOI: 10.1016/j.ajhg.2019.11.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development and Structural Evaluation of N‐Alkylated trans‐2‐Phenylcyclopropylamine‐Based LSD1 Inhibitors (2020)
  • Author(s): Niwa Hideaki、Sato Shin、Handa Noriko、Sengoku Toru、Umehara Takashi、Yokoyama Shigeyuki
  • Journal Title: ChemMedChem Volume: 15 Issue: 9 Pages: 787-793
  • DOI: 10.1002/cmdc.202000014
  • Peer Reviewed
• [Journal Article] Ribosomal synthesis and de novo discovery of bioactive foldamer peptides containing cyclic β-amino acids (2020)
  • Author(s): Katoh Takayuki、Sengoku Toru、Hirata Kunio、Ogata Kazuhiro、Suga Hiroaki
  • Journal Title: Nature Chemistry Volume: 12 Issue: 11 Pages: 1081-1088
  • DOI: 10.1038/s41557-020-0525-1
  • Peer Reviewed
• [Journal Article] The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype (2019)
  • Author(s): Yigit Gokhan、Saida Ken、DeMarzo Danielle、Miyake Noriko、Fujita Atsushi、Yang Tan Tiong、White Susan M.、Wadley Alexandrea、Toliat Mohammad R.、Motameny Susanne、Franitza Marek、Stutterd Chloe A.、Chong Pin F.、Kira Ryutaro、et al.
  • Journal Title: Human Mutation Volume: 41 Issue: 3 Pages: 591-599
  • DOI: 10.1002/humu.23964
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Reply to "Reduced CYFIP2 Stability by Arg87 Variants Causing Human Neurological Disorders" (2019)
  • Author(s): Nakashima M, Ogata K, Saitsu H, Matsumoto N
  • Journal Title: Annals of Neurology Volume: 86 Issue: 5 Pages: 805-806
  • DOI: 10.1002/ana.25599
  • Peer Reviewed
• [Journal Article] Ataxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42 (2019)
  • Author(s): Hashiguchi S, Doi H, Kunii M, Nakamura Y, Shimuta M, （32名略） Ishikawa T, Tanaka F
  • Journal Title: Neurobiology of Disease Volume: 130 Pages: 104516-104516
  • DOI: 10.1016/j.nbd.2019.104516
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing (2019)
  • Author(s): Iwama Kazuhiro、Mizuguchi Takeshi、Miyatake Satoko、Matsumoto Naomichi、et al
  • Journal Title: Journal of Medical Genetics Volume: - Issue: 6 Pages: 396-407
  • DOI: 10.1136/jmedgenet-2018-105775
  • Peer Reviewed / Open Access
• [Journal Article] Germline-Derived Gain-of-Function Variants of Gsα-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis (2019)
  • Author(s): Miyado Mami、Fukami Maki、Takada Shuji、Terao Miho、Nakabayashi Kazuhiko、Hata Kenichiro、Matsubara Yoichi、Tanaka Yoko、Sasaki Goro、Nagasaki Keisuke、Shiina Masaaki、Ogata Kazuhiro、Masunaga Youhei、Saitsu Hirotomo、Ogata Tsutomu
  • Journal Title: Journal of the American Society of Nephrology Volume: 30 Issue: 5 Pages: 877-889
  • DOI: 10.1681/asn.2018121268
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylation of an intrinsically disordered region of Ets1 shifts a multi-modal interaction ensemble to an out-inhibitory state. (2018)
  • Author(s): Kota Kasahara, Masaaki Shiina, Junichi Higo, Kazuhiro Ogata, Haruki Nakamura.
  • Journal Title: Nucleic Acids Research Volume: 46 Issue: 5 Pages: 2243-2251
  • DOI: 10.1093/nar/gkx1297
  • Peer Reviewed / Open Access
• [Journal Article] De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy (2018)
  • Author(s): Nakashima Mitsuko、Kato Mitsuhiro、Aoto Kazushi、Shiina Masaaki、Belal Hazrat、Mukaida Souichi、Kumada Satoko、Sato Atsushi、Zerem Ayelet、Lerman-Sagie Tally、Lev Dorit、Leong Huey Yin、Tsurusaki Yoshinori、Mizuguchi Takeshi、Miyatake Satoko、Miyake Noriko、Ogata Kazuhiro、Saitsu Hirotomo、Matsumoto Naomichi
  • Journal Title: Annals of Neurology Volume: 83 Issue: 4 Pages: 794-806
  • DOI: 10.1002/ana.25208
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders (2018)
  • Author(s): Mizuguchi Takeshi、Kurahashi Hirokazu、et al.
  • Journal Title: Human Molecular Genetics Volume: 27 Issue: 8 Pages: 1421-1433
  • DOI: 10.1093/hmg/ddy052
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A homozygous NOP14 variant is likely to cause recurrent pregnancy loss (2018)
  • Author(s): Suzuki Toshifumi、Behnam Mahdiyeh、Ronasian Firooze、Salehi Mansoor、Shiina Masaaki、Koshimizu Eriko、Fujita Atsushi、Sekiguchi Futoshi、Miyatake Satoko、Mizuguchi Takeshi、Nakashima Mitsuko、Ogata Kazuhiro、Takeda Satoru、Matsumoto Naomichi、Miyake Noriko
  • Journal Title: Journal of Human Genetics Volume: 63 Issue: 4 Pages: 425-430
  • DOI: 10.1038/s10038-018-0410-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia. (2018)
  • Author(s): Cho K, Yamada M, Agematsu K, Kanegane H, Miyake N, Ueki M, Akimoto T, Kobayashi N, Ikemoto S, Tanino M, Fujita A, Hayasaka I, Miyamoto S, Tanaka-Kubota M, Nakata K, Shiina M, Ogata K, Minakami H, Matsumoto N, Ariga T.
  • Journal Title: Am J Hum Genet Volume: 102 Issue: 3 Pages: 480-486
  • DOI: 10.1016/j.ajhg.2018.01.019
  • NAID: 120006502505
  • Peer Reviewed / Open Access
• [Journal Article] De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders (2018)
  • Author(s): Akita Tenpei、Aoto Kazushi、Kato Mitsuhiro、Shiina Masaaki、Mutoh Hiroki、Nakashima Mitsuko、Kuki Ichiro、Okazaki Shin、Magara Shinichi、Shiihara Takashi、Yokochi Kenji、Aiba Kaori、Tohyama Jun、Ohba Chihiro、Miyatake Satoko、Miyake Noriko、Ogata Kazuhiro、Fukuda Atsuo、Matsumoto Naomichi、Saitsu Hirotomo
  • Journal Title: Annals of Clinical and Translational Neurology Volume: 5 Issue: 3 Pages: 280-296
  • DOI: 10.1002/acn3.528
  • Peer Reviewed / Open Access
• [Journal Article] De novo mutations of the ATP6V1A gene cause developmental encephalopathy with epilepsy (2018)
  • Author(s): Fassio Anna、Esposito Alessandro、Kato Mitsuhiro、Saitsu Hirotomo、et al.
  • Journal Title: Brain Volume: 141 Issue: 6 Pages: 1703-1718
  • DOI: 10.1093/brain/awy092
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel CYCS mutation in the α‐helix of the CYCS C‐terminal domain causes non‐syndromic thrombocytopenia (2018)
  • Author(s): Uchiyama Yuri、Yanagisawa Kunio、Kunishima Shinji、Shiina Masaaki、Ogawa Yoshiyuki、Nakashima Mitsuko、Hirato Junko、Imagawa Eri、Fujita Atsushi、Hamanaka Kohei、Miyatake Satoko、Mitsuhashi Satomi、Takata Atsushi、Miyake Noriko、Ogata Kazuhiro、Handa Hiroshi、Matsumoto Naomichi、Mizuguchi Takeshi
  • Journal Title: Clinical Genetics Volume: 94 Issue: 6 Pages: 548-553
  • DOI: 10.1111/cge.13423
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Biallelic COLGALT1 variants are associated with cerebral small vessel disease (2018)
  • Author(s): Miyatake Satoko、Schneeberger Sacha、Koyama Norihisa、Yokochi Kenji、Ohmura Kayo、、Hennet Thierry、Matsumoto Naomichi、et al
  • Journal Title: Annals of Neurology Volume: 84 Issue: 6 Pages: 843-853
  • DOI: 10.1002/ana.25367
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome (2018)
  • Author(s): Fujita Atsushi、Tsukaguchi Hiroyasu、Koshimizu Eriko、Nakazato Hitoshi、Itoh Kyoko、Kuraoka Shohei、Komohara Yoshihiro、Shiina Masaaki、Nakamura Shohei、Kitajima Mika、Tsurusaki Yoshinori、Miyatake Satoko、Ogata Kazuhiro、Iijima Kazumoto、Matsumoto Naomichi、Miyake Noriko
  • Journal Title: Annals of Neurology Volume: 84 Issue: 6 Pages: 814-828
  • DOI: 10.1002/ana.25370
  • Peer Reviewed
• [Journal Article] GRIN2D variants in three cases of developmental and epileptic encephalopathy (2018)
  • Author(s): Tsuchida Naomi、Hamada Keisuke、Shiina Masaaki、Kato Mitsuhiro、Kobayashi Yu、Tohyama Jun、Kimura Kazue、Hoshino Kyoko、Ganesan Vigneswari、Teik Keng W.、Nakashima Mitsuko、Mitsuhashi Satomi、Mizuguchi Takeshi、Takata Atsushi、Miyake Noriko、Saitsu Hirotomo、Ogata Kazuhiro、Miyatake Satoko、Matsumoto Naomichi
  • Journal Title: Clinical Genetics Volume: 94 Issue: 6 Pages: 538-547
  • DOI: 10.1111/cge.13454
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Thioether Macrocyclic Peptides Selected against TET1 Compact Catalytic Domain Inhibit TET1 Catalytic Activity (2018)
  • Author(s): Nishio Kosuke、Belle Roman、Katoh Takayuki、Kawamura Akane、Sengoku Toru、Hanada Kazuharu、Ohsawa Noboru、Shirouzu Mikako、Yokoyama Shigeyuki、Suga Hiroaki
  • Journal Title: ChemBioChem Volume: 19 Issue: 9 Pages: 979-985
  • DOI: 10.1002/cbic.201800047
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural basis of protein arginine rhamnosylation by glycosyltransferase EarP (2018)
  • Author(s): Sengoku Toru、Suzuki Takehiro、Dohmae Naoshi、Watanabe Chiduru、Honma Teruki、Hikida Yasushi、Yamaguchi Yoshiki、Takahashi Hideyuki、Yokoyama Shigeyuki、Yanagisawa Tatsuo
  • Journal Title: Nature Chemical Biology Volume: 14 Issue: 4 Pages: 368-374
  • DOI: 10.1038/s41589-018-0002-y
  • Peer Reviewed
• [Journal Article] A novel GFI1B mutation at the first zinc finger domain causes congenital macrothrombocytopenia (2017)
  • Author(s): Uchiyama Y, Ogawa Y, Kunishima S, Shiina M, Nakashima M, Yanagisawa K, Yokohama A, Imagawa E, Miyatake S, Mizuguchi T, Takata A, Miyake N, Ogata K, Handa H, Matsumoto N
  • Journal Title: British Journal of Haematology Volume: 印刷中 Issue: 6 Pages: 843-847
  • DOI: 10.1111/bjh.14710
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A novel missense mutation affecting the same amino acid as the recurrent PACS1 mutation in Schuurs-Hoeijmakers syndrome (2017)
  • Author(s): Miyake N, Ozasa S, Mabe H, Kimura S, Shiina M, Imagawa E, Miyatake S, Nakashima M, Mizuguchi T, Takata A, Ogata K, Matsumoto N
  • Journal Title: Clinical Genetics Volume: 93 Issue: 4 Pages: 929-930
  • DOI: 10.1111/cge.13105
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel mutation in SLC1A3 causes episodic ataxia (2017)
  • Author(s): Iwama Kazuhiro、Iwata Aya、Shiina Masaaki、Mitsuhashi Satomi、Miyatake Satoko、Takata Atsushi、Miyake Noriko、Ogata Kazuhiro、Ito Shuichi、Mizuguchi Takeshi、Matsumoto Naomichi
  • Journal Title: Journal of Human Genetics Volume: 63 Issue: 2 Pages: 207-211
  • DOI: 10.1038/s10038-017-0365-z
  • Peer Reviewed
• [Presentation] リボソーム合成と生理活性フォルダマーペプチドの発見 (2021)
  • Author(s): 仙石 徹
  • Organizer: 第59回SPring-8先端利用技術ワークショップ/大阪大学タンパク質研究所セミナー
• [Presentation] 乳酸に対する新たな視点とその応用 (2020)
  • Author(s): 仙石 徹
  • Organizer: 木原記念横浜生命科学振興財団オンラインセミナー
• [Presentation] Nrf2-小Mafヘテロ二量体による標的DNA認識機構のFMO法（フラグメント分子軌道法）による解析 (2019)
  • Author(s): 仙石 徹，森脇寛智，渡邊千鶴，本間光貴，緒方一博
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Analysis of target DNA recognition mechanism by Nrf2-small Maf heterodimer using fragment molecular orbital (FMO) method (2019)
  • Author(s): Sengoku T, Moriwaki H, Watanabe C, Honma T, Ogata K
  • Organizer: CBI学会2019年大会
• [Presentation] トリプトファンプレニル基転移酵素の結晶構造解析 (2019)
  • Author(s): 濱田恵輔，岡田千佳子，井上澄香，後藤佑樹，菅 裕明，緒方一博，仙石 徹
  • Organizer: 第92回日本生化学会大会
• [Presentation] メチル基を数える: ヒストンH4K20のメチル化状態を特異的に認識する抗体の構造 (2018)
  • Author(s): 仙石 徹，渡邉千鶴，馬場しほ，本間光貴，緒方一博，木村 宏，横山茂之
  • Organizer: 第91回日本生化学会大会
• [Presentation] Structural basis for the recognition of the antioxidant response element by the Nrf2-MafG heterodimer. (2018)
  • Author(s): Sengoku T, Shiina M, Uchiyama A, Baba S, Okada C, Sato K, Hamada K, Ogata K
  • Organizer: 第41回日本分子生物学会年会
• [Remarks] 横浜市立大学大学院医学研究科生化学教室
  • URL: http://www-user.yokohama-cu.ac.jp/~seika/index.html