Analysis of a transcriptional regulatory mechanism by histone/p53 demethylase complex

• Project/Area Number: 22790101
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: UMEHARA Takashi 独立行政法人理化学研究所, システム研究チーム, 上級研究員 (20415095)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2010: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 遺伝子発現 / エピジェネティクス / エピゲノム / クロマチン / 染色体 / ヒストン / ヌクレオソーム / 結晶構造解析 / 転写

Research Abstract

This study aimed to analyze a regulatory mechanism of human chromatin transcription. Pertaining to LSD1 that demethylates nuclear factors such as human histone H3 and tumor suppressor gene product p53, we solved LSD1 crystal structures in complex with small molecular weight inhibitors that had been previously identified by our group. We revealed that one of the LSD1 inhibitors showed good cell permeability and three of the inhibitors exhibited gene expression regulatory activities.

Research Products

• [Journal Article] FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure. (2012)
  • Author(s): Hino S, Sakamoto A, Nagaoka K, Anan K, Wang Y, Mimasu S, Umehara T, Yokoyama S, Kosai K, and Nakao M
  • Journal Title: Nat. Commun Volume: 27;3 Issue: 1 Pages: 758-758
  • DOI: 10.1038/ncomms1755
  • Peer Reviewed
• [Journal Article] A tandem insertion vector for large-scale preparation of nucleosomal DNA (2012)
  • Author(s): Wakamori, M.,# Umehara, T.,# Yokoyama, S
  • Journal Title: Anal. Biochem Volume: 423(1) Pages: 184-186
  • Peer Reviewed
• [Journal Article] A tandem insertion vector for large-scale preparation of nucleosomal DNA (2012)
  • Author(s): Wakamori, M., Umehara, T., Yokoyama, S.
  • Journal Title: Anal.Biochem. Volume: (印刷中) Issue: 1 Pages: 184-186
  • DOI: 10.1016/j.ab.2012.01.010
  • Peer Reviewed
• [Journal Article] FAD-dependent lysine demethylase LSD1 regulates cellular energy expenditure (2012)
  • Author(s): Hino, S., Sakamoto, A., Nagaoka, K., Wang, Y., Mimasu, S., Umehara, T., Yokoyama, S., Kosai, K.I., Nakao, M.
  • Journal Title: Nature Communications Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Genetic-code evolution for protein synthesis with non-natural amino acids (2011)
  • Author(s): Mukai, T., Yanagisawa, T., Ohtake, K., Wakamori, M., Adachi, J., Hino, N., Sato, A., Kobayashi, T., Hayashi, A., Shirouzu, M., Umehara, T., Yokoyama, S., Sakamoto, K
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 411(1) Pages: 757-761
  • Peer Reviewed
• [Journal Article] Real-time imaging of histone H4K12-specific acetylation determines the modes of action of histone deacetylase and bromodomain inhibitors (2011)
  • Author(s): Ito, T., Umehara, T., Sasaki, K., Nakamura, Y., Nishino, N., Terada, T., Shirouzu, M., Padmanabhan, B., Yokoyama, S., Ito, A., Yoshida, M
  • Journal Title: Chemistry & Biology Volume: 18(4) Pages: 495-507
  • Peer Reviewed
• [Journal Article] Crystallographic study of a site-specifically cross-linked protein complex with a genetically incorporated photo-reactive amino acid (2011)
  • Author(s): Sato, S., Mimasu, S., Sato, A., Hino, N., Sakamoto, K., Umehara, T., Yokoyama, S
  • Journal Title: Biochemistry Volume: 50(2) Pages: 250-257
  • Peer Reviewed
• [Journal Article] Real-time imaging of histone H4K12-specific acetylation determines the modes of action of histone deacetylase and bromodomain inhibitors (2011)
  • Author(s): Ito, T., Umehara, I., Sasaki, K., Nakamura, Y., Nishino, N., Terada, T., Shirouzu, M., Padmanabhan, B., Yokoyama, S., Ito, A., Yoshida, M.
  • Journal Title: Chemistry & Biology Volume: 18 Issue: 4 Pages: 495-507
  • DOI: 10.1016/j.chembiol.2011.02.009
  • Peer Reviewed
• [Journal Article] Genetic-code evolution for protein synthesis with non-natural amino acids (2011)
  • Author(s): Mukai, T., Yanagisawa, T., Ohtake, K., Wakamori, M., Adachi, J., Hino, N., Sato, A., Kobayashi, T., Hayashi, A., Shirouzu, M., Umehara, T., Yokoyama, S., Sakamoto, K.
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 411 Issue: 4 Pages: 757-761
  • DOI: 10.1016/j.bbrc.2011.07.020
  • Peer Reviewed
• [Journal Article] Crystallographic study of a site-specifically cross-linked protein complex with a genetically incorporated photo-reactive amino acid (2011)
  • Author(s): Sato, S., et al.
  • Journal Title: Biochemistry Volume: 50 Pages: 250-257
  • Peer Reviewed
• [Journal Article] Structural implications for K5/K12-di-acetylated histone H4 recognition by the second bromodomain of BRD2 (2010)
  • Author(s): Umehara, T., Nakamura, Y., Wakamori, M., Ozato, K., Yokoyama, S., Padmanabhan, B
  • Journal Title: FEBS Lett Volume: 584(18) Pages: 3901-3908
  • Peer Reviewed
• [Journal Article] A series of bacterial co-expression vectors with rare-cutter recognition sequences (2010)
  • Author(s): Wakamori, M., Umehara, T., Yokoyama S
  • Journal Title: Protein Expr. Purif Volume: 74(1) Pages: 88-98
  • Peer Reviewed
• [Journal Article] Structurally designed trans-2-phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1(# corresponding authors) (2010)
  • Author(s): Mimasu, S., Umezawa, N., Sato, S., Higuchi, T.,# Umehara, T.,# Yokoyama, S
  • Journal Title: Biochemistry Volume: 49(30) Pages: 6494-6503
  • Peer Reviewed
• [Journal Article] Structurally designed trans-2-phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1 (2010)
  • Author(s): Mimasu, S., et al.
  • Journal Title: Biochemistry Volume: 49 Pages: 6494-6503
  • Peer Reviewed
• [Journal Article] A series of bacterial co-expression vectors with rare-cutter recognition sequences (2010)
  • Author(s): Wakamori, M., et al.
  • Journal Title: Protein Expression and Purification Volume: 74 Pages: 88-98
  • Peer Reviewed
• [Journal Article] Structural implications for K5/K12-di-acetylated histone H4 recognition by the second bromodomain of BRD2 (2010)
  • Author(s): Umehara, T., et al.
  • Journal Title: FEBS Letters Volume: 584 Pages: 3901-3908
  • Peer Reviewed
• [Presentation] エピジェネティクス阻害剤開発のための新しいケミカルツール (2012)
  • Author(s): 梅原崇史,横山茂之
  • Organizer: 第132回日本薬学会年会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-30
• [Presentation] エピヌクレオソームを標的とした構造生物学 (2012)
  • Author(s): 梅原崇史
  • Organizer: 構造生物学社会連携講座研究成果報告会
  • Place of Presentation: 東京
  • Year and Date: 2012-03-24
• [Presentation] アセチル化ヒストンを認識するブロモドメインの結晶構造解析と阻害剤の開発 (2012)
  • Author(s): 梅原崇史,中村祥浩,寺田貴帆,白水美香子, Padmanabhan B.,横山茂之
  • Organizer: 第29回Photon Factoryシンポジウム
  • Place of Presentation: つくば
  • Year and Date: 2012-03-15
• [Presentation] 部位特異的なアセチル化を含む『エピヌクレオソーム』の試験管内再構成 (2011)
  • Author(s): 梅原崇史,若森昌聡,須賀則之,安達仁朗,向井崇人,寺田貴帆,白水美香子,坂本健作,横山茂之
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-15
• [Presentation] 部位特異的なアセチル化を含む『エピヌクレオソーム』の試験管内再構成 (2011)
  • Author(s): 梅原崇史, 若森昌聡, 須賀則之, 安達仁朗, 向井崇人, 寺田貴帆, 白水美香子, 坂本健作, 横山茂之
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2011-12-15
• [Presentation] 「KLFとエピゲノムを中心としたがん・心臓病関連因子複合体の構造・機能解析」,「未解決のがんと心臓病を撲滅する最適医療開発」 (2011)
  • Author(s): 梅原崇史
  • Organizer: 最先端研究開発支援プログラム,第1回公開シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2011-09-28
• [Presentation] KLFとエピゲノムを中心としたがん・心臓病関連因子複合体の構造・機能解析 (2011)
  • Author(s): 梅原崇史
  • Organizer: 最先端研究開発支援プログラム「未解決のがんと心臓病を撲滅する最適医療開発」第1回公開シンポジウム
  • Place of Presentation: 東京都文京区
  • Year and Date: 2011-09-28
• [Presentation] In vitro reconstitution of 'epi-nucleosome' core particles for broad epigenetic analyses (2011)
  • Author(s): Umehara, T., Wakamori, M., Sato, S., Terada, T., Shirouzu, M., Sakamoto, K., Yokoyama, S
  • Organizer: KEY Forum in Developmental Biology and Regenerative Medicine
  • Place of Presentation: Kumamoto, Japan
  • Year and Date: 2011-09-08
• [Presentation] In vitro reconstitution of 'epi-nucleosome' core particles for broad epigenetic analyses (2011)
  • Author(s): Umehara, T., Wakamori, M., Sato, S., Terada, T., Shirouzu, M., Sakamoto, K., Yokoyama, S.
  • Organizer: KEY Forum in Developmental Biology and Regenerative Medicine
  • Place of Presentation: 熊本県熊本市
  • Year and Date: 2011-09-08
• [Presentation] In vitro reconstitution of 'epi-nucleosome' core particles (2011)
  • Author(s): Umehara, T., Wakamori, M., Sato, S., Terada, T., Shirouzu, M., Sakamoto, K., Yokoyama, S
  • Organizer: FASEB Summer Research Conference on Epigenetics, Chromatin & Transcription
  • Place of Presentation: Snowmass Village, CO, USA
  • Year and Date: 2011-08-04
• [Presentation] In vitro reconstitution of 'epi-nucleosome' core particles (2011)
  • Author(s): Umehara, T., Wakamori, M., Sato, S., Terada, T., Shirouzu, M., Sakamoto, K., Yokoyama, S.
  • Organizer: FASEB Summer Research Conference on Epigenetics, Chromatin & Transcription
  • Place of Presentation: 米国・コロラド州Snowmass Village
  • Year and Date: 2011-08-04
• [Presentation] エピジェネティック情報を持つヌクレオソームコア粒子の試験管内再構成 (2011)
  • Author(s): 梅原崇史, 若森昌聡, 佐藤心, 寺田貴帆, 白水美香子, 坂本健作, 横山茂之
  • Organizer: 第5回日本エピジェネティクス研究会年会
  • Place of Presentation: 熊本県熊本市
  • Year and Date: 2011-05-20
• [Presentation] エピジェネティック情報を持つヌクレオソームコア粒子の試験管内再構成 (2011)
  • Author(s): 梅原崇史,若森昌聡,佐藤心,寺田貴帆,白水美香子,坂本健作,横山茂之
  • Organizer: 第5回日本エピジェネティクス研究会年会
  • Place of Presentation: 熊本
  • Year and Date: 2011-05-19
• [Presentation] ヒストン脱メチル化酵素LSD1/KDM1を阻害する化合物の開発 (2010)
  • Author(s): 梅原崇史,三桝信哉,梅澤直樹,佐藤心,樋口恒彦,横山茂之
  • Organizer: 第33回日本分子生物学会年会・第81回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-10
• [Presentation] ヒストン脱メチル化酵素LSD1/KDM1を阻害する化合物の開発 (2010)
  • Author(s): 梅原崇史, 他
  • Organizer: 第33回日本分子生物学会年会・第81回日本生化学会大会
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2010-12-10
• [Presentation] Structural biology and molecular imaging (2010)
  • Author(s): Umehara, T., Yokoyama, S
  • Organizer: 6th Hangzhou International Molecular Imaging Conference(HIMIC2010)
  • Place of Presentation: Hangzhou, China
  • Year and Date: 2010-09-12
• [Presentation] Structural biology and molecular imaging (2010)
  • Author(s): Takashi Umehara
  • Organizer: 6th Hangzhou International Molecular Imaging Conference (HIMIC2010)
  • Place of Presentation: 中国・浙江省杭州市
  • Year and Date: 2010-09-12
• [Presentation] Structure-based development of specific inhibitors for histone demethylase LSD1/KDM1 (2010)
  • Author(s): Umehara, T., Mimasu, S., Umezawa, N., Sato, S., Higuchi, T., Yokoyama, S
  • Organizer: 9th EMBL Conference of Transcription and Chromatin
  • Place of Presentation: Heidelberg, Germany
  • Year and Date: 2010-08-29
• [Presentation] Structure-based development of specific inhibitors for histone demethylase LSD1/KDM1 (2010)
  • Author(s): Umehara, T., et al.
  • Organizer: 9th EMBL Conference of Transcription and Chromatin
  • Place of Presentation: ドイツ・ハイデルベルグ
  • Year and Date: 2010-08-29
• [Presentation] Structural study on Kruppel-like factors and KLF-associated factors (2010)
  • Author(s): Umehara, T
  • Organizer: FASEB Summer Research Conference on Biology and Pathobiology of Kruppel-like Factors(KLFs)
  • Place of Presentation: Steamboat Springs, CO, USA
  • Year and Date: 2010-08-09
• [Presentation] Structural study on Kruppel-like factors and KLF-associated factors (2010)
  • Author(s): Takashi Umehara
  • Organizer: 2010 FASEB Summer Research Conference on Biology and Pathobiology of Kruppel-like Factors
  • Place of Presentation: 米国・コロラド州Steamboat Springs
  • Year and Date: 2010-08-09