A search for target genes of aberrant histone methylation diseases and the establishment of drug discovery platform based on elucidation of pathological conditions

• Project/Area Number: 26670169
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human genetics
• Research Institution: Saga University
• Principal Investigator: Soejima Hidenobu 佐賀大学, 医学部, 教授 (30304885)
• Co-Investigator(Renkei-kenkyūsha): MATSUMOTO Naomichi 横浜市立大学, 大学院医学研究科, 教授 (80325638) ; YOSHIURA Ko-ichiro 長崎大学, 原爆後障害医療研究所, 教授 (00304931)
• Research Collaborator: HIGASHIMOTO Ken 佐賀大学, 医学部, 助教 (30304885) ; YATSUKI Hitomi 佐賀大学, 医学部, 技術専門職員 ; WATANABE Hidetaka 佐賀大学, 大学院・医学系研究科, 大学院生
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ヒストンメチル化酵素 / DNAメチル化 / ソトス症候群 / ゲノムインプリンティング / 遺伝子発現 / 歌舞伎症候群

Outline of Final Research Achievements

We screened methylation status of imprinting associated differentially methylated regions (DMRs) in patients with Sotos syndrome, an aberrant histone methylation disease, to find NSD1 target genes and elucidate pathological conditions. We found two DMRs reduced methylation in about half of patients. Cells cultured with 5-Aza-CdR revealed the increased expression of imprinted genes with the reduced methylation of the DMRs. It was suggested that NSD1 mutations induced hypomethylation of the DMRs followed by the increased expression of the imprinted genes. Aberrant expression of the genes were probably involved in the pathological conditions of Sotos syndrome. In addition, we established the cell lines, which expressed FLAG tagged NSD1 protein. We plan to identify the NSD1 target genes using the cell lines.

Research Products

• [Journal Article] Identification of consensus motifs associated with mitotic recombination and clinical characteristics in patients with paternal uniparental isodisomy of chromosome 11. (2016)
  • Author(s): Ohtsuka Y, Higashimoto K, Oka T, Yatsuki H, Jozaki K, Maeda T, Kawahara K, Hamasaki Y, Matsuo M, Nishioka K, Joh K, Mukai T, Soejima H.
  • Journal Title: Hum Mol Genet. Volume: 25 Issue: 7 Pages: 1406-19
  • DOI: 10.1093/hmg/ddw023
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The HUS1B promoter is hypomethylated in the placentas of low-birth-weight infants. (2016)
  • Author(s): Rumbajan JM, Yamaguchi Y, Nakabayashi K, Higashimoto K, Yatsuki H, Nishioka K, Matsuoka K, Aoki S, Toda S, Takeda S, Seki H, Hatada I, Hata K, Soejima H, Joh K.
  • Journal Title: Gene. Volume: 583 Issue: 2 Pages: 141-146
  • DOI: 10.1016/j.gene.2016.02.025
  • Peer Reviewed
• [Journal Article] Novel Nonsense Mutation in the NLRP7 Gene Associated with Recurrent Hydatidiform Mole. (2015)
  • Author(s): Ito Y, Maehara K, Kaneki E, Matsuoka K, Sugahara N, Miyata T, Kamura H, Yamaguchi Y, Kono A, Nakabayashi K, Migita O, Higashimoto K, Soejima H, Okamoto A, Nakamura H, Kimura T, Wake N, Taniguchi T, Hata K.
  • Journal Title: Gynecol Obstet Invest Volume: Epub ahead of print Issue: 4 Pages: 1-6
  • DOI: 10.1159/000441780
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Beckwith-Wiedemann 症候群（BWS） (2015)
  • Author(s): 東元健、副島英伸
  • Journal Title: 臨床画像 Volume: 31 Pages: 189-191
• [Journal Article] Beckwith-Wiedemann syndrome (2015)
  • Author(s): 東元健、副島英伸
  • Journal Title: 日本臨床 家族性腫瘍学―家族性腫瘍の最新研究動向― Volume: 73 Pages: 59-63
• [Journal Article] Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. (2014)
  • Author(s): Ohnishi K, Semi K, Yamamoto T, Shimizu M, Tanaka A, Mitsunaga K, Okita K, Osafune K, Arioka Y, Maeda T, Soejima H, Moriwaki H, Yamanaka S, Woltjen K, Yamada Y.
  • Journal Title: Cell Volume: 156 Issue: 4 Pages: 663-677
  • DOI: 10.1016/j.cell.2014.01.005
  • Peer Reviewed
• [Journal Article] Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of the human imprintome and suggests a germline methylation independent establishment of imprinting. (2014)
  • Author(s): Court F, Tayama C, Romanelli V, Martin-Trujillo A, Iglesias-Platas I, Okamura K, Sugahara N, Simon C, Moore H, Harness J, Keirstead H, Vicente Sanchez-Mut J, Kaneki E, Lapunzina P, Soejima H, Wake N, Esteller M, Ogata T, Hata K, Nakabayashi K, Monk D*
  • Journal Title: Genome Res Volume: in press Issue: 4 Pages: 554-569
  • DOI: 10.1101/gr.164913.113
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive and quantitative multilocus methylation analysis reveals the susceptibility of specific imprinted differentially methylated regions (DMRs) to aberrant methylation in Beckwith-Wiedemann syndrome with epimutations (2014)
  • Author(s): Maeda T, Higashimoto K, Jozaki K, Hitomi H, Nakabayashi K, Makita Y, Tonoki H, Okamoto N, Takada F, Ohashi H, Migita M, Kosaki R, Matsubara K, Ogata T, Matsuo M, Hamasaki Y, Ohtsuka Y, Nishioka K, Joh K, Mukai T, Hata K, Soejima H
  • Journal Title: Genet Med Volume: 16(12) Issue: 12 Pages: 903-912
  • DOI: 10.1038/gim.2014.46
  • Peer Reviewed / Open Access
• [Journal Article] Fibroadenoma in a Beckwith-Wiedemann syndrome with paternal uniparental disomy of chromosome 11p15.5. (2014)
  • Author(s): Takama Y, Kubota A, Nakayama M, Higashimoto K, Jozaki K, Soejima H.
  • Journal Title: Pediatrics International Volume: 56 Issue: 6 Pages: 931-934
  • DOI: 10.1111/ped.12406
  • Peer Reviewed
• [Journal Article] Autosomal recessive cystinuria caused by genome-wide paternal uniparental isodisomy in a patient with Beckwith-Wiedemann syndrome. (2014)
  • Author(s): Ohtsuka Y, Higashimoto K, Sasaki K, Jozaki K, Yoshinaga H, Okamoto N, Takama Y, Kubota A, Nakayama M, Yatsuki H, Nishioka K, Joh K, Mukai T, Yoshiura KI, Soejima H.
  • Journal Title: Clin Genet. Volume: 8 Issue: 3 Pages: 1-1
  • DOI: 10.1111/cge.12496
  • Peer Reviewed / Open Access
• [Journal Article] A Clinical Study of Beckwith-Wiedemann Syndrome (2014)
  • Author(s): 加藤大貴、井村英人、東元健、八木ひとみ、芝崎龍典、古川博雄、新美照幸、藤原 久美子、鈴木聡、外山佳孝、南克浩、井上知佐子、早川統子、副島英伸、夏目長門
  • Journal Title: Journal of Japanese Cleft Palate Association Volume: 39 Issue: 1 Pages: 21-27
  • DOI: 10.11224/cleftpalate.39.21
  • NAID: 130004567685
  • ISSN: 0386-5185, 2186-5701
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Beckwith-Wiedemann症候群 (2014)
  • Author(s): 東元健、副島英伸
  • Journal Title: 周産期医学 Volume: 44 Pages: 258-260
• [Journal Article] 間葉性異形成胎盤Placental mesenchymal dysplasia (PMD)の診断と原因遺伝子 (2014)
  • Author(s): 大場隆、片渕秀隆、副島英伸
  • Journal Title: 病理と臨床 Volume: 32 Pages: 535-540
• [Journal Article] A novel de novo point mutation of OCT-binding site in the IGF2/H19-imprinting control region in a patient with Beckwith-Wiedemann syndrome. (2013)
  • Author(s): Higashimoto K, Jozaki K, Kosho T, Matsubara K, Sato T, Yamada D, Yatsuki H, Maeda T, Ohtsuka Y, Nishioka K, Joh K, Koseki H, Ogata T, SoejimaH*
  • Journal Title: Clin Genet Volume: in press Issue: 6 Pages: 539-544
  • DOI: 10.1111/cge.12318
  • Peer Reviewed / Open Access
• [Presentation] DIS3L2複合ヘテロ変異を同定した長期生存Perlman症候群の１例 (2016)
  • Author(s): 長崎啓祐、東元健、相馬規子、今村勝、齋藤昭彦、副島英伸
  • Organizer: 第39回日本小児遺伝学会学術集会
  • Place of Presentation: 慶應義塾大学三田キャンパス
  • Year and Date: 2016-12-09
• [Presentation] ソトス症候群とベックウィズ・ビーデマン症候群でオーバーラップする表現型の原因探索 (2016)
  • Author(s): 渡邊英孝、東元健、三宅紀子、前田寿幸、樋高秀憲、青木早織、八木ひとみ、西岡憲一、城圭一郎、松本直通、副島英伸
  • Organizer: 第39回日本小児遺伝学会学術集会
  • Place of Presentation: 慶應義塾大学三田キャンパス
  • Year and Date: 2016-12-09
• [Presentation] CTCF遺伝子欠失を認めた2女児の臨床的および遺伝学的検討 (2016)
  • Author(s): 堀いくみ, 河村理恵, 中林一彦, 家田大輔, 大橋圭, 根岸豊, 服部文子, 杉尾嘉嗣, 涌井敬子, 黒澤健司, 秦健一郎，副島英伸, 齋藤伸治
  • Organizer: 第39回日本小児遺伝学会学術集会
  • Place of Presentation: 慶應義塾大学三田キャンパス
  • Year and Date: 2016-12-09
• [Presentation] NSD1ハプロ不全はDNAメチル化インプリント異常と遺伝子発現異常を惹起する (2016)
  • Author(s): 渡邊英孝、東元健、三宅紀子、前田寿幸、樋高秀憲、青木早織、八木ひとみ、西岡憲一、城圭一郎、森田純代、堀居拓郎、木村美香、畑田出穂、松本直通、副島英伸
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] Comprehensive methylation analysis of imprinting-associated differentially methylated regions in colorectal cancer. (2016)
  • Author(s): Hidaka H, Higashimoto K, Takara Y, Takedomi H, Okamoto N, Kawakubo H, Yamamoto K, Yamanouchi K, Koga Y, Iwakiri R, Noshiro H, Fujimoto K, Soejima H
  • Organizer: 24th United European Gastroenterology Week
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2016-10-15
  • Int'l Joint Research
• [Presentation] 大腸癌におけるインプリントDMRの包括的メチル化解析（Comprehensive methylation analysis of imprinting-associated differentially methylated regions in colorectal cancer） (2016)
  • Author(s): 樋高秀憲、東元健、古賀靖大、副島英伸．
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06
• [Presentation] 間葉性異形成胎盤のゲノム・エピゲノム解析 (2016)
  • Author(s): 青木早織、東元 健、樋高秀憲、大塚泰史、渡邊英孝、三嶋博之、吉浦孝一郎、大場 隆、片渕秀隆、副島英伸
  • Organizer: 第10回日本エピジェネティクス研究会年会
  • Place of Presentation: 千里ライフサイエンスセンター
  • Year and Date: 2016-05-19
• [Presentation] 大腸癌におけるインプリントDMRの包括的メチル化解析 (2016)
  • Author(s): 樋高秀憲、東元健、青木早織、渡邊英孝、前田寿幸、古賀靖大、岩切龍一、能城浩和、藤本一眞、副島英伸
  • Organizer: 第10回日本エピジェネティクス研究会年会
  • Place of Presentation: 千里ライフサイエンスセンター
  • Year and Date: 2016-05-19
• [Presentation] Comprehensive methylation analysis of imprinting-associated differentially methylated regions in colorectal cancer. (2016)
  • Author(s): Hidaka H, Higashimoto K, Aoki S, Watanabe H, Yatsuki H, Nishioka K, Joh K, Maeda T, Koga Y, Iwakiri R, Noshiro H, Fujimoto K, Soejima H.
  • Organizer: The 13th International Congress of Human Genetics.
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Aberrant methylation at imprinted DMRs is associated with placental mesenchymal dysplasia. (2016)
  • Author(s): Aoki S, Higashimoto K, Hidaka H, Watanabe H, Ohtsuka Y, Mishima H, Yoshiura KI, Yatsuki H, Nishioka K, Joh K, Ohba T, Katabuchi H, Soejima H.
  • Organizer: The 13th International Congress of Human Genetics.
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Novel MCA/ID syndrome with ASH1L mutation. (2016)
  • Author(s): Okamoto N, Miya F, Nishioka K, Soejima H, Tsunoda T, Kato M, Saitoh S, Yamasaki M, Kanemura Y, Kosaki K.
  • Organizer: The 13th International Congress of Human Genetics.
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] DNAメチル化異常不一致を示す一卵性2絨毛膜2羊膜双胎のBeckwith-Wiedemann syndrome (2016)
  • Author(s): 東元 健、八木ひとみ、副島英伸
  • Organizer: 第23回遺伝性疾患に関する出生前診断研究会
  • Place of Presentation: 長崎大学医学部
• [Presentation] 間葉性異形成胎盤の分子遺伝学的解析 (2015)
  • Author(s): 青木早織、東元健、樋高秀憲、渡邊英孝、大塚泰史、三嶋博之、吉浦孝一郎、八木ひとみ、西岡憲一、城圭一郎、大場隆、片渕秀隆、副島英伸
  • Organizer: 第23回日本胎盤学会学術集会
  • Place of Presentation: JA共済ビル（東京）
  • Year and Date: 2015-11-05
• [Presentation] インプリンティング関連疾患のゲノム・エピゲノム解析 (2015)
  • Author(s): 副島英伸
  • Organizer: 第19回日本内分泌病理学会
  • Place of Presentation: アバンセ（佐賀市）
  • Year and Date: 2015-10-24
  • Invited
• [Presentation] 大腸癌におけるインプリントDMRの包括的メチル化解析 (2015)
  • Author(s): 樋高秀憲、東元健、青木早織、渡邊英孝、八木ひとみ、西岡憲一、城圭一郎、前田寿幸、古賀靖大、岩切龍一、能城浩和、藤本一眞、副島英伸
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2015-10-14
• [Presentation] Beckwith-Wiedemann症候群の原因となる片親性父性ダイソミーの切断点領域の解析 (2015)
  • Author(s): 大塚泰史、岡岳彦、川原弘三、八木ひとみ、東元健、副島英伸
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2015-10-14
• [Presentation] 間葉性異形成胎盤のゲノム・エピゲノム解析 (2015)
  • Author(s): 青木早織、東元健、樋高秀憲、渡邊英孝、大塚泰史、三嶋博之、吉浦孝一郎、八木ひとみ、西岡憲一、城圭一郎、大場隆、片渕秀隆、副島英伸
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2015-10-14
• [Presentation] 間葉性異形成胎盤におけるインプリントDMRのエピジェノタイプ変化 (2015)
  • Author(s): 青木早織、東元健、樋高秀憲、大塚泰史、三嶋博之、吉浦孝一郎、大場隆、片渕秀隆、副島英伸
  • Organizer: 第22回遺伝性疾患に関する出生前診断研究会
  • Place of Presentation: 九州大学
  • Year and Date: 2015-10-03
• [Presentation] シスチン尿症を伴うゲノムワイド父性片親性ダイソミー症例の遺伝子解析 (2015)
  • Author(s): 副島英伸
  • Organizer: 第22回日本遺伝子診療学会大会
  • Place of Presentation: かながわ労働プラザ（横浜）
  • Year and Date: 2015-07-17
• [Presentation] Beckwith-Wiedemann症候群と診断した1絨毛膜2羊膜性双胎の一女児例 (2015)
  • Author(s): 吉村 歩、松原理沙、田中秀門、今市悠太郎、吉田悟、荻田薫、野村武雅、側島健宏、松下博亮、白井憲司、南野初香、元重京子、木部哲也、東元健、副島英伸
  • Organizer: 第137回日本小児科学会静岡地方会
  • Place of Presentation: 静岡県職員会館
  • Year and Date: 2015-06-07
• [Presentation] Beckwith-Wiedemann症候群エピ変異症例におけるインプリントDMRの包括的メチル化解析 (2015)
  • Author(s): 前田寿幸、城崎幸介、八木ひとみ、東元 健、松尾宗明、副島英伸
  • Organizer: 第57回日本小児神経学会学術集会
  • Place of Presentation: 帝国ホテル大阪（大阪）
  • Year and Date: 2015-05-28
• [Presentation] Clinical and histopathlogical features of placental mesenchymal dysplasia. (2015)
  • Author(s): Aoki S, Ohba T, Okajima M, Higashimoto K, Soejima H, Katabuchi H.
  • Organizer: The 6th Asan-Kumamoto Joint Symposium
  • Place of Presentation: Kumamoto, Japan
  • Year and Date: 2015-05-23
  • Int'l Joint Research
• [Presentation] Beckwith-Wiedemann症候群における新生児期低血糖合併機序の検討 (2015)
  • Author(s): 長嶋一昭、田中大祐、東元 健、八木ひとみ、杉崎 和、田原 裕美子、副島英伸、稲垣暢也
  • Organizer: 第112回日本内科学会総会
  • Place of Presentation: 京都
  • Year and Date: 2015-04-10
• [Presentation] Small for gestational age（SGA）胎盤のゲノムワイドDNAメチル化解析 (2014)
  • Author(s): 副島英伸、Rumbajan Janette Mareska、畑田出穂、中林一彦、泰健一郎、青木茂久、関博之、竹田省、城圭一郎
  • Organizer: 日本人類遺伝学会第59回大会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-19 – 2014-11-22
• [Presentation] Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of the human imprintome and suggests a germline methylation independent control of imprinting in the placenta． (2014)
  • Author(s): 中林一彦、Court Franck、田山千春、Romanelli Valeria、副島英伸、和氣徳夫、Esteller Manel、緒方勤、秦健一郎、Monk David．
  • Organizer: 第8回日本エピジェネティクス研究会年会
  • Place of Presentation: 東京大学
  • Year and Date: 2014-05-25 – 2014-05-27
• [Presentation] Ash1l methylates Lys36 of histone H3 independently of transcriptional elongation to counteract Polycomb silencing. (2014)
  • Author(s): Kenichi Nishioka、Hitomi Miyazaki, Ken Higashimoto, Yukari Yada, Takaho A. Endo, Jafar Sharif, Manabu Nakayama, Hidenobu Soejima, Haruhiko Koseki, Susumu Hirose．
  • Organizer: 第8回日本エピジェネティクス研究会年会
  • Place of Presentation: 東京大学
  • Year and Date: 2014-05-25 – 2014-05-27
• [Presentation] Beckwith-Wiedemann症候群と肝芽腫におけるmultiple methylation defectの解析 (2014)
  • Author(s): 前田寿幸、Rumbajan Janette Mareska、東元 健、中林一彦、八木ひとみ、秦健一郎、城圭一郎、副島英伸．
  • Organizer: 第8回日本エピジェネティクス研究会年会
  • Place of Presentation: 東京大学
  • Year and Date: 2014-05-25 – 2014-05-27
• [Presentation] Beckwith-Wiedemann症候群における片親性父性ダイソミーの遺伝学多様性と臨床症状との関連 (2014)
  • Author(s): 大塚泰史
  • Organizer: 第69回佐賀小児科地方会
  • Place of Presentation: 佐賀大学
  • Year and Date: 2014-04-05
• [Presentation] Beckwith-Wiedemann症候群におけるインプリントDMRのマルチローカスメチル化解析 (2014)
  • Author(s): 前田寿幸
  • Organizer: 第69回佐賀小児科地方会
  • Place of Presentation: 佐賀大学
  • Year and Date: 2014-04-05
• [Book] エピジェネティクスの産業応用 第Ⅳ編疾患エピゲノム研究 第12章インプリンティング疾患のエピジェネティクス (2014)
  • Author(s): 副島英伸
  • Total Pages: 14
  • Publisher: シーエムシー出版
• [Book] Beckwith-Wiedemann症候群．別冊日本臨牀 新領域別症候群シリーズNo.29 神経症候群（第２版）Ⅳ-その他の神経疾患を含めて- (2014)
  • Author(s): 東元健、副島英伸
  • Total Pages: 4
  • Publisher: 日本臨牀社
• [Book] Silver-Russell症候群．別冊日本臨牀 新領域別症候群シリーズNo.29 神経症候群（第２版）Ⅳ-その他の神経疾患を含めて- (2014)
  • Author(s): 前田寿幸、副島英伸
  • Total Pages: 4
  • Publisher: 日本臨牀社
• [Remarks] 佐賀大学医学部分子生命科学講座分子遺伝学・エピジェネティクス分野
  • URL: http://www.biomol.med.saga-u.ac.jp/mbg/index.htm