Novel epigenetic regulation of the gene expression program by chromosome dynamics

• Project/Area Number: 23390068
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Shiga University of Medical Science (2013); Kyoto University (2011-2012)
• Principal Investigator: AGATA YASUTOSHI 滋賀医科大学, 医学部, 教授 (60263141)
• Co-Investigator(Renkei-kenkyūsha): IKAWA Tomokatsu 理化学研究所 統合生命医科学研究センター, 免疫細胞再生研究YCIラボ, 研究員 (60450392) ; SATOH Fumiaki 京都大学, 医学研究科, 准教授 (20467426)
• Project Period (FY): 2011-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥19,760,000 (Direct Cost: ¥15,200,000、Indirect Cost: ¥4,560,000); Fiscal Year 2013: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2012: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2011: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: 染色体ダイナミクス / エピジェネティクス / コヒーシン / Rad21 / CTCF / E2A / ChIP-Seq / 染色体構造変化 / インシュレーター / クロマチン / 遺伝子発現 / 3C アッセイ / Mediator / 造血系前駆細胞

Outline of Final Research Achievements

Cohesin essential for chromosome cohesion and the insulator component CTCF regulate the expression of genes, which are critical for cell differentiation, by chromosome dynamics. To identify genes that are regulated by these proteins and also critical for T cell differentiation, we performed ChIP-Seq analyses using the EBF-KO progenitor cell line, which differentiates to T cells upon Notch stimulation, and found that the cohesin subunit Rad21 and CTCF bound to the genes such as Tcf7 and Bcl11b, master regulators of T cell differentiation. We thus depleted Rad21 and CTCF by knockdown and found that Tcf7 and Bcl11b expression was further increased and T cell differentiation was facilitated. In contrast, when we depleted E2A essential for TCRβ locus contraction, Bcl11b and Notch target genes were downregulated and T cell differentiation was abrogated. These results suggest that Rad21/CTCF and E2A regulate T cell differentiation in a negative or positive manner, respectively.

Research Products

• [Journal Article] The E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis. (2015)
  • Author(s): Miyazaki M, Miyazaki K, Chen S, Chandra V, Wagatsuma K, Agata Y, Rodewald HR, Saito R, Chang AN, Varki N, Kawamoto H, Murre C.
  • Journal Title: Genes Dev. Volume: 29 Issue: 4 Pages: 409-425
  • DOI: 10.1101/gad.255331.114
  • Peer Reviewed / Open Access
• [Journal Article] Crucial role of the Rap G protein signal in Notch activation and leukemogenicity of T-cell acute lymphoblastic leukemia. (2015)
  • Author(s): Doi K, Imai T, Kressler C, Yagita H, Agata Y, Vooijs M, Hamazaki Y, Inoue J, Minato N.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 7978-7985
  • DOI: 10.1038/srep07978
  • NAID: 120005555511
  • Peer Reviewed / Open Access
• [Journal Article] High expression of nuclear factor 90 (NF90) leads to mitochondrial degradation in skeletal and cardiac muscles (2013)
  • Author(s): Takuma Higuchi
  • Journal Title: PLoS One Volume: 7 Issue: 8 Pages: e43340-e43340
  • DOI: 10.1371/journal.pone.0043340
  • Peer Reviewed
• [Journal Article] E2A and CBP/p300 act in synergy to promote chromatin accessibility of the immunoglobulin | locus. (2012)
  • Author(s): Sakamoto, S., ffakae, K., Anzai, Y., Murai, K., Tamaki, N., Miyazaki, M., Miyazaki, K., Romanow, W. J., Ikawa, T., Kitamura, D., Yanagihira, I., Minato, N., Murre, C., Agata, Y
  • Journal Title: J. Immunol Volume: 188 Issue: 11 Pages: 5547-5560
  • DOI: 10.4049/jimmunol.1002346
  • Peer Reviewed
• [Journal Article] Reciprocal control of G1-phase progression is required for Th-POK/Runx3-mediated CD4/8 thymocyte cell fate decision. (2012)
  • Author(s): Sato T, Chiba T, Ohno S, Sato C, Sugoh T, Miyashita K, Akatsuka H, Hozumi K, Okada Y, Iida Y, Akatsuka A, Agata Y, Chiba M, Kohu K, Satake M, Tanabe H, Saya H, Habu S.
  • Journal Title: J Immunol. Volume: 189 Issue: 9 Pages: 4426-4436
  • DOI: 10.4049/jimmunol.1102748
  • Peer Reviewed
• [Journal Article] Imatinib mesylate directly impairs class switch recombination through downregulation of AID. (2012)
  • Author(s): Kawamata T, Lu J, Sato T, Tanaka M, Nagaoka H, Agata Y, Toyoshima T, Yokoyama K, Oyaizu N, Nakamura N, Ando K, Tojo A, Kotani A
  • Journal Title: Blood Volume: 119 Issue: 13 Pages: 3123-3127
  • DOI: 10.1182/blood-2011-01-327932
  • Peer Reviewed
• [Journal Article] The opposing roles of the transcription factor E2A and its antagonist Id3 that orchestrate and enforce the naive fate of T cells. (2011)
  • Author(s): Miyazaki M, Rivera RR, Miyazaki K, Lin YC, Agata Y, Murre C
  • Journal Title: Nat Immunol. Volume: 12 Issue: 10 Pages: 992-1001
  • DOI: 10.1038/ni.2086
  • Peer Reviewed
• [Presentation] コヒーシン/CTCFとE2AによるT細胞初期分化の制御 (2014)
  • Author(s): 安齋悠樹、山下政克、伊川友活、増田喬子、河本 宏、湊 長博、縣 保年
  • Organizer: 第24回 Kyoto T Cell Conference
  • Place of Presentation: 京都平安ホテル
  • Year and Date: 2014-05-16 – 2014-05-17
• [Presentation] 発生段階特異的なTCRγ遺伝子再構成における転写抑制因子Gfi-1の役割 (2011)
  • Author(s): 若江亨祥、坂本修士、山下政克、中山俊憲、湊長博、縣保年
  • Organizer: 第19回Kyoto T Cell Conference
  • Place of Presentation: 日本、京都
  • Year and Date: 2011-06-11
• [Remarks] 滋賀医科大学 生化学・分子生物学講座 分子生理化学部門
  • URL: http://www.shiga-med.ac.jp/~hqbioch1/