Analysis of transcription factory and epigenomic modification in inflammatory stimulation driven transcription wave

2012 Fiscal Year Final Research Report

• Project/Area Number: 22310117
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Genome biology
• Research Institution: The University of Tokyo
• Principal Investigator: WADA Youichiro 東京大学, 先端科学技術研究センター, 特任准教授 (10322033)
• Co-Investigator(Kenkyū-buntansha): KANKI Yasuharu 東京大学, 先端科学技術研究センター, 特任研究員 (00534869) ; KHORO Takahide 東京大学, 医学部付属病院, 特任助教 (40401046) ; OHTA Yoshihiro 東京大学, 先端科学技術研究センター, 特任研究員 (80436592)
• Project Period (FY): 2010 – 2012
• Keywords: RNA ポリメレース / TNFα / ヒストン修飾 / 内皮細胞

Research Abstract

Chronic inflammation of endothelial cell is the first stage ofatherogenesis. We applied an experimental model using endothelial cells with representative inflammatory stimulant, tumor necrosis factor-alpha (TNFα), and to dissect detailedmechanism of induction and reduction of more than 500 genes. To obtain a comprehensive view of a single transcription cycle caused by TNFα in time course manner, we switched onfive long (>100 kbp) genes with TNFα and monitored genomic localization of nascent RNA, RNA Pol II, insulators, and histone modifications. Activation triggers a wave of transcriptionthat sweeps along the genes, and Pol II tends to stall at cohesin/CTCF binding sites. Chromatin conformation capture (3C), both conventional and quantitative data, revealedco-localization of actively transcribed genes. These results suggested that fine-tuning of TNFα responsive genes is achieved by selected number of transcription complexes, whichprovide platform for both transcription and splic ng. By virtue of whole genome chromatininteraction analysis with paired end tag sequencing (ChIA-PET) detailed chromatin structureanalysis was made possible, and time course data on stimulated endothelium sheds light ondynamic chromatin structure change within half an hour.

Research Products

• [Journal Article] TNF alpha signals through specialized factories where responsive coding and miRNA genes are transcribed. (2012)
  • Author(s): Papantonis, A., Kohro, T., Baboo, S., Larkin, J.D., Deng, B., Short, P., Tsutsumi, S., Taylor, S.,Kanki, Y., Kobayashi, M., Li, G., Poh, H., Ruan,X., Aburatani, H., Ruan, Y., Kodama, T., Wada,Y., and Cook, P. R.
  • Journal Title: The EMBO journal Volume: 31 Pages: 4404-4414
  • DOI: DOI:10.1038/emboj.2012.288.
• [Journal Article] Distribution of histone3 lysine 4 trimethylation at T3-responsive loci in the heart during reversible changes in gene expression. (2012)
  • Author(s): Pandya, K., Kohro, T., Mimura, I., Kobayashi, M., *Wada, Y. Kodama, T., and Smithies, O.
  • Journal Title: Gene Expr Volume: 15 Pages: 183-198
• [Journal Article] Path-preference cellular-automaton model for traffic flow through transit points and its application to the transcription process in human cells. (2012)
  • Author(s): Ohta, Y., Nishiyama, A., Wada, Y., Ruan, Y., Kodama, T., Tsuboi, T., Tokihiro, T., and *Ihara, S.
  • Journal Title: Phys Rev E Stat Nonlin Soft Matter Phys Volume: 86 Pages: 021918.
  • DOI: DOI:10.1103/PhysRevE.86.021918
• [Journal Article] Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. (2012)
  • Author(s): Mimura, I., Nangaku, M., Kanki, Y., Tsutsumi, S., Inoue, T., Kohro, T., Yamamoto, S., Fujita, T., Shimamura, T., Suehiro, J., Taguchi, A., Kobayashi, M., Tanimura, K., Inagaki, T., Tanaka, T., Hamakubo, T., Sakai, J., Aburatani, H., Kodama, T., and Wada, Y.
  • Journal Title: Molecular and Cellular Biology Volume: 32 Pages: 3018-3032
  • DOI: DOI:10.1128/MCB.06643-11.
• [Journal Article] Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. (2012)
  • Author(s): Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T,Mogushi K, Tanaka H, Osawa T, Kanki Y, et al
  • Journal Title: Nature Communications Volume: 6;3 Pages: 883
  • DOI: DOI:10.1038/ncomms1892.
• [Journal Article] A multi-gene transcriptional profiling approach to the discovery of cell signature markers. (2011)
  • Author(s): Wada, Y., Li, D., Merley, A., Zukauskas, A., Aird, W. C., Dvorak, H. F., and *Shih, S. C.
  • Journal Title: Cytotechnology Volume: 63 Pages: 25-33
• [Journal Article] Pathophysiological response to hypoxia - from the molecular mechanisms of malady to drug discovery: epigenetic regulation of the hypoxic response via hypoxia-inducible factor and histone modifying enzymes. (2011)
  • Author(s): Mimura, I., Tanaka, T., Wada, Y., Kodama, T., and *Nangaku, M.
  • Journal Title: Journal of pharmacological sciences Volume: 115 Pages: 453-458
• [Journal Article] Epigenetically coordinated GATA2 binding is necessary for endothelium-specific endomucin expression. (2011)
  • Author(s): Kanki, Y., Kohro, T., Jiang, S., Tsutsumi, S., Mimura, I., Suehiro, J., Wada, Y., Ohta, Y., Ihara, S., Iwanari, H., Naito, M., Hamakubo, T., Aburatani, H., Kodama, T., and *Minami, T.
  • Journal Title: The EMBO journal Volume: 30 Pages: 2582-2595
  • DOI: DOI:10.1038/emboj.2011.173
• [Journal Article] Mitochondrial DNA polymerase editing mutation, PolgD257A, reduces the diabetic phenotype of Akita male mice by suppressing appetite. (2011)
  • Author(s): Fox, R., Kim, H. S., Reddick, R. L., Kujoth, G. C., Prolla, T. A., Tsutsumi, S., Wada, Y., Smithies, O., and *Maeda, N.
  • Journal Title: Proceedings of the National Academy ofSciences of the United States of America Volume: 108 Pages: 8779-8784
  • DOI: DOI:10.1073/pnas.1106344108
• [Journal Article] ChIP-seq reveals cell type-specific binding patterns of BMP-specific Smads and a novel binding motif. (2011)
  • Author(s): Morikawa M, Kanki Y et al.
  • Journal Title: Nucleic Acids Research Volume: 39 Pages: 8712-27
  • DOI: DOI:10.1093/nar/gkr572
• [Journal Article] Sev ere dermatitis with loss of epidermal Langerh ans cells in human and mouse zinc deficiency. (2011)
  • Author(s): Kawamura T, Ohta Y, et al.
  • Journal Title: The Journal of Clinical Investigation Volume: 84 Pages: 722-732
  • DOI: DOI:10.1172/JCI58618
• [Journal Article] Cellular-automaton model of the cooperative dynamics of RNA polymerase II during transcription in human cells. (2011)
  • Author(s): Ohta Y, et al.
  • Journal Title: Physical Review E Volume: 84 Pages: 041922-2-15
  • DOI: DOI:10.1103/PhysRevE.84.041922
• [Journal Article] Proteomic analysis of native hepatocyte nuclear factor-4alpha (HNF4alpha) isoforms, phosphorylation status, and interactive cofactors. (2011)
  • Author(s): Daigo, K, Kawamura T, Ohta Y, et al.
  • Journal Title: The Journal of Biological Chemistry Volume: 286 Pages: 674-686
• [Journal Article] Genome-wide approaches reveal functional interleukin-4-inducible STAT6 binding to the vascular cell adhesion molecule 1 promoter. (2011)
  • Author(s): Tozawa H, Kanki Y, Wada Y, et al.
  • Journal Title: Molecular and Cellular Biology Volume: vol.31 Pages: 2196-209
  • DOI: DOI:10.1128/MCB.01430-10
• [Journal Article] Active RNA polymerases (2010)
  • Author(s): Papantonis, A., Larkin, J. D., Wada, Y., Ohta, Y., Ihara, S., Kodama, T., and Cook, P. R.
  • Journal Title: mobile or immobile molecular machines PLoS biology 8 Volume: e1000419.
• [Presentation] A wave of nascent transcription on activated big genes in human endothelial cells is suggestive to dynamic chromatin movement caused by transcription factories (2013)
  • Author(s): 和田洋一郎
  • Organizer: 第90回日本生理学会大会
  • Place of Presentation: 東京
  • Year and Date: 20130327-0329
• [Presentation] Comprehensive analyses revealed the epigenetic switch during the endothelial cell differentiation (2013)
  • Author(s): 神吉康晴
  • Organizer: 第12回日本再生医療学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20130321-0323
• [Presentation] Comprehensive analyses revealed the epigenetic switch during the endothelial cell differentiation (2013)
  • Author(s): 神吉康晴
  • Organizer: 第12回日本再生医療学会
  • Place of Presentation: 横浜
  • Year and Date: 20130321-0323
• [Presentation] Three Dimensional Chromatin Architecture Correlates with Two Opposite Transcription Factors, which contributes the Cell Specificity (2013)
  • Author(s): 神吉康晴
  • Organizer: The 5th HOPE meeting
  • Place of Presentation: グランドプリンスホテル新高輪
  • Year and Date: 20130225-0302
• [Presentation] Two transcription factors mediated opposite chromatin conformation correlates with endothelial cell specificity (2012)
  • Author(s): 神吉康晴
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 20121211-14
• [Presentation] Molecular mechanism about sustained VCAM-1 induction by the transcriptome and epigenomic analyses. (2012)
  • Author(s): 神吉康晴
  • Organizer: 第20回日本血管生物医学会学術集会 (The 10th Korea-Japan Joint Symposium on Vascular Biology)
  • Place of Presentation: 徳島あわぎんホール
  • Year and Date: 20121205-1207
• [Presentation] The initiation step about the changes of transcription factor bindings and histone modifications is involved in sustained gene inductions. (2012)
  • Author(s): 神吉康晴
  • Organizer: Keystone Symposia 2013 Aging and Diseases of Aging
  • Place of Presentation: Sheraton Miyako Hotel Tokyo
  • Year and Date: 20121022-1027
• [Presentation] Regulation of the Endothelial-Mesenchymal Transition(EndMT) (2012)
  • Author(s): 神吉康晴
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 20120919-0921
• [Presentation] 転写過程の超離散モデリングとシミュレーション (2012)
  • Author(s): 大田佳宏
  • Organizer: 京都大学数理解析研究所研究集会
  • Place of Presentation: 京都大学益川ホール
  • Year and Date: 20120820-0822
• [Presentation] Epigenetic Switch on the Differentiation of Mouse Vascular Endothelial Cells (2012)
  • Author(s): 神吉康晴
  • Organizer: International Society for Stem Cell Research 10th Annual Meeting
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20120613-0616
• [Presentation] 心血管系エピゲノム研究を通して得られた転写メカニズムの新しい概念 (2012)
  • Author(s): 和田洋一郎
  • Organizer: 第六回日本エピジェネティクス研究会年会
  • Place of Presentation: 東京
  • Year and Date: 20120514-0515
• [Presentation] Epigenetically coordinated GATA2 bindings are necessary for the endothelial cell specificity (2012)
  • Author(s): 神吉康晴
  • Organizer: 第六回日本エピジェネティクス研究会年会
  • Place of Presentation: 東京
  • Year and Date: 20120514-0515
• [Presentation] A wave of nascent transcription on activated big genes in human endothelial cells (2012)
  • Author(s): 和田洋一郎
  • Organizer: Keystone Symposia 2012 Chromatin Dynamics
  • Year and Date: 20120117-22
• [Presentation] Epigenetic Regulation in Endothelial-cell Specific Genes by Transcription factor GATA2 Binding Regions (2012)
  • Author(s): 神吉康晴
  • Organizer: Keystone Symposia 2012 Epigenomics (J3)
  • Place of Presentation: Keystone Resort, Keystone, Colorado, USA
  • Year and Date: 20120117-1122
• [Presentation] ChIP-sequence Reveals Functional Interleukin-4-Inducible STAT6 Binding to the Vascular Cell Adhesion Molecule 1 Promoter (2012)
  • Author(s): 神吉康晴
  • Organizer: 第12回東京大学生命科学シンポジウム
  • Place of Presentation: 東京大学
  • Year and Date: 2012-06-30
• [Presentation] Functional Roles of GATA2 in Vascular Biology (2011)
  • Author(s): 神吉康晴
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20111213-1216
• [Presentation] Identification of novel MEF2C binding site indispensable for KLF4 induction in endothelial cells by statin treatment. (2011)
  • Author(s): 前島崇司、和田洋一郎
  • Organizer: 第19回日本血管生物医学会学術集会
  • Place of Presentation: 東京ステーションコンファレンス、東京
  • Year and Date: 20111208-1210
• [Presentation] Epigenetic Framework in Vascular Endothelial Cells (2011)
  • Author(s): 神吉康晴
  • Organizer: 第19回日本血管生物医学会学術集会
  • Place of Presentation: 東京ステーションカンファレンス、東京都
  • Year and Date: 20111208-1210
• [Presentation] A wave of nascent transcr iption on activated big genes in human endothelial cells (2011)
  • Author(s): 和田洋一郎
  • Organizer: International Symposi um on the Physicochemical Field for Gen etic Activities
  • Place of Presentation: 淡路夢舞台国際会議場(兵庫県)
  • Year and Date: 20111124-1126
• [Presentation] Epigenetically Coordinate GATA2 Binding Regions are Necessary for the Determination of the Endothelial Cell Specificity (2011)
  • Author(s): 神吉康晴
  • Organizer: The Second Pacific Symposium on Vascular Biology
  • Place of Presentation: Jeju Island(Shilla Hotel), Korea
  • Year and Date: 20111030-1102
• [Presentation] Renewal of histone modification during a wave of transcription caused by inflammatory stimulation in endothelial cells. (2011)
  • Author(s): 和田洋一郎
  • Organizer: 第5回日本エピジェネティクス研究会
  • Place of Presentation: KKRホテル、熊本市
  • Year and Date: 20110519-0520
• [Presentation] Epigenetically Coordinate GATA2 Cistrome is Necessary for the Det ermination of the Endothelial Cell Spec ificity (2011)
  • Author(s): 神吉康晴
  • Organizer: CDB symposium 2011
  • Place of Presentation: 理化学研究所 発生・再生科学総合 研究センター(兵庫県)
  • Year and Date: 20110314-0315
• [Presentation] High Density Spatial and Temporal Simulation Reveals Transcriptional Dynamics (2011)
  • Author(s): 大田佳宏、Yoshihiro
  • Organizer: The Pacific Symposium on Biocomputing (PSB) 2011
  • Place of Presentation: Kona, USA.
  • Year and Date: 20110104-0108
• [Presentation] 疾患と発生を繋ぐエピゲノムー血管疾患の解明に向けてー (2011)
  • Author(s): 神吉康晴
  • Organizer: Genomic Sciences Research Complex(GSC)七夕ミーティング2011
  • Place of Presentation: 理化学研究所横浜研究所、神奈川県
  • Year and Date: 2011-08-25
• [Presentation] 超高速シーケンサーが明らかにした転写に伴うダイナミックな染色体構造変化と新たな転写装置の概念 (2011)
  • Author(s): 和田洋一郎
  • Organizer: 第2回ARTセミナー
  • Place of Presentation: 岡山大学
  • Year and Date: 2011-05-25
• [Presentation] 動脈硬化誘導刺激に応じて血管内皮細胞で複数遺伝子を同時に転写する装置の同定 (2010)
  • Author(s): 和田洋一郎
  • Organizer: 第33回日本分子生物学会年会、第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 20101207-1210
• [Presentation] GATA2 occupancies differ f rom each cell type, which is correlated with epigenetic modifications and gene expression profiles in cell-type speci fic manner (2010)
  • Author(s): 神吉康晴
  • Organizer: 第33回日本分子生物学会年会、第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 20101207-1210
• [Presentation] Epigenetically coordinate GATA2 occupancy is necessary for the determination of the endothelial cell specificity (2010)
  • Author(s): 神吉康晴
  • Organizer: 第18回日本血管生物医学会学術集会
  • Place of Presentation: 梅田スカイビル
  • Year and Date: 20101201-1203
• [Presentation] Epigenetically coordinate GATA2 bindings in endothelium is necess ary for the determination of the endoth elial cell specificity (2010)
  • Author(s): 神吉康晴
  • Organizer: 2010年度がん若手ワークショップ
  • Place of Presentation: アートランドホテル蓼科(長野県)
  • Year and Date: 20100901-0904
• [Presentation] 血管内皮細胞における転写因子GATA2の機能解析 (2010)
  • Author(s): 神吉康晴
  • Organizer: 第22回高遠シンポジウ ム
  • Place of Presentation: 高遠さくらホテル
  • Year and Date: 20100819-0820