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The Regulome controls adaptive lymphocyte development and DNA recombinase Rag1/Rag2 expression

Research Project

Project/Area Number 19H03487
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 49070:Immunology-related
Research InstitutionKyoto University

Principal Investigator

Miyazaki Masaki  京都大学, ウイルス・再生医科学研究所, 准教授 (80403632)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords獲得免疫 / Rag1 Rag2 / T, B細胞 / 遺伝子再構成 / エンハンサー / ゲノム構造 / 転写因子 / E2A / adaptive lymphocyte / T cell and B cell / Rag1 and Rag2 expression / enhancer regulation / super-enhancer formation / V(D)J DNA recombination / 獲得免疫リンパ球 / Rag遺伝子 / 3次元ゲノム構造変換 / 転写因子E2A / 3次元ゲノム構造 / 獲得免疫リンパ球分化 / Rag1/Rag2遺伝子発現制御 / 3Dゲノム構造制御 / T細胞分化 / B細胞分化 / Rag1/Rag2遺伝子 / Regulame / リンパ球分化 / エンハンサー調節 / 3Dゲノム
Outline of Research at the Start

感染に対する生体防御機構である免疫反応は、獲得免疫と自然免疫細胞の協調により成立する。獲得免疫はT,B細胞による抗原特異的な炎症反応に依存し、これは遺伝子再構成による抗原受容体分子の形成が必須である。言い換えれば、遺伝子再構成分子の発現が獲得免疫を特徴付けていると言える。Rag1/Rag2は遺伝子再構成に必須の分子であり、T,B細胞の分化段階でのみ発現する特殊な遺伝子である。本研究課題では、この特異的な遺伝子の発現調節を、エンハンサー領域の3Dゲノム構造による変化を軸に解析を試みる、非常に独創的な研究である。

Outline of Final Research Achievements

Adaptive immunity relies on Rag-mediated assembly of T cell receptor (TCR) and immunoglobulin (Ig) genes. The expression of the Rag1 and Rag2 (Rag1/2) is stringently controlled in a cell type-specific manner during lymphocyte development. However, it remains unclear how Rag1/2 expression is regulated at a mechanistic level. Here, we used multiple in vivo approaches to identify T and B cell-specific regulatory elements that form Rag super-enhancers (SEs) and are essential for V(D)J recombination of TCR and Ig genes. Binding of E2A/E-proteins to the regulatory elements induces cohesin-mediated looping between enhancer, promoter, and anchor regions, resulting in large-scale topological changes for Rag SE formation. Also, E2A and E-protein binding facilitates compartment switching of the Rag1/2 gene cluster. Overall, our results demonstrate the importance of E-proteins in orchestrating the SEs that drive the tightly regulated Rag1/2 expression in adaptive immunity.

Academic Significance and Societal Importance of the Research Achievements

T細胞受容体やB細胞の抗体の遺伝子再構成は、獲得免疫による多様で特異的な免疫反応に必須であり、この再構成を行うRag1/2の発現制御機構を解明することは、獲得免疫の本質をどうやって手に入れたのかを解明する重要な鍵となる。本研究ではT, B細胞におけるRag1/2遺伝子のエンハンサー領域を同定し、その領域が転写因子E2Aによるエンハンサー活性制御に依存していることを見出した。このことは、獲得免疫の特徴であるRag1/2発現が特定の転写因子により誘導され、これがVDJ遺伝子再構成という多様性獲得に大きく貢献しており、この分子機構が獲得免疫の始まりであると提唱したい。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (8 results)

All 2021 2020 2019

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (5 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results)

  • [Journal Article] The Interplay Between Chromatin Architecture and Lineage-Specific Transcription Factors and the Regulation of Rag Gene Expression.2021

    • Author(s)
      Miyazaki K., Miyazaki M.
    • Journal Title

      Frontiers in Immunology,

      Volume: 12

    • DOI

      10.3389/fimmu.2021.659761

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Evolution of Rag Gene Enhancers and Transcription Factor E and Id proteins in the Adaptive Immune System.2021

    • Author(s)
      Yoshikawa G, Miyazaki K, Ogata H*, Miyazaki M
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 11 Pages: 5888-5888

    • DOI

      10.3390/ijms22115888

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The transcription factor E2A activates multiple enhancers that drive Rag expression in developing T and B cells2020

    • Author(s)
      Miyazaki Kazuko、Watanabe Hitomi、Yoshikawa Genki、Chen Kenian、Hidaka Reiko、Aitani Yuki、Osawa Kai、Takeda Rie、Ochi Yotaro、Tani-ichi Shizue、Uehata Takuya、Takeuchi Osamu、Ikuta Koichi、Ogawa Seishi、Kondoh Gen、Lin Yin C.、Ogata Hiroyuki、Miyazaki Masaki
    • Journal Title

      Science Immunology

      Volume: 5 Issue: 51 Pages: 1455-1455

    • DOI

      10.1126/sciimmunol.abb1455

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] E2A specifies adaptive immunity by instructing large-scale topological changes for Rag gene super-enhancer formation.2021

    • Author(s)
      Masaki Miyazaki
    • Organizer
      The 94th Annual Meeting of the Japanese Biochemical Society.
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Conserved two E-box sequences neighboring the Rag1-promoter is critically required for the initiation of Rag1 gene expression upon T and B cell lineage commitment; Distinct gene regulation mediated by enhancers and promoter for adaptive immunity2021

    • Author(s)
      Masaki Miyazaki
    • Organizer
      The 50th Annual Meeting of the Japanese Society for Immunology.
    • Related Report
      2021 Annual Research Report
  • [Presentation] E2A specifies adaptive immunity by instructing large-scale topological changes for Rag gene super-enhancer formation.2020

    • Author(s)
      Masaki Miyazaki.
    • Organizer
      Cold Spring Harbor Laboratory Meeting
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The establishment of 3D genome structure for Rag1/Rag2 expression mediated by E2A/E-protein enhancer activity2019

    • Author(s)
      宮崎 正輝
    • Organizer
      第48回日本免疫学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] The establishment of 3D genome structure for Rag1/Rag2 expression mediated by E2A/E-protein enhancer activity2019

    • Author(s)
      Masaki Miyazaki
    • Organizer
      FASEB Science Reserach Conference
    • Related Report
      2019 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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