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Analysis of the biological significance and molecular mechanisms of meiosis-specific production of Mga variants.

Research Project

Project/Area Number 20K16147
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionSaitama Medical University

Principal Investigator

Uranishi Kousuke  埼玉医科大学, 医学部, 助教 (40783238)

Project Period (FY) 2020-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords減数分裂 / PRC1.6 / Mga / Meiosin / Stra8 / bHLHZ / T-box / ES細胞 / 生殖細胞 / PRC1
Outline of Research at the Start

私たちは、減数分裂期の生殖細胞において、Mgaの減数分裂期特異的なスプライシングが起こり、C末端が欠損したMgaの新規バリアント(MgaΔC)が発現していることを発見した。このMgaΔCはMaxとの結合領域(bHLH-LZ)を欠損しており、それ故、染色体上のE-box配列に結合することができない。ES細胞におけるMgaのbHLH-LZ領域欠損において、減数分裂関連遺伝子の上昇が見られることから、この、野生型MgaからMgaΔCへのスプライシング変化は生殖細胞の減数分裂起程において正に作用すると考えられる。そこで、本研究では、このMgaΔCの作用機序および発現機構を明らかにし、生殖細胞分化の分子機構の解明を目指す。

Outline of Final Research Achievements

Our understanding of the molecular mechanisms that prevent precocious meiotic onset by PRC1.6 is far from complete. Moreover, how germ cells impede the function of PRC1.6 for physiological meiotic onset remains totally obscure. In this research project, I have demonstrated that two distinct DNA binding domains of Mga, a scaffolding component of PRC1.6 enables the complex to repress numerous meiosis-related genes. I have also demonstrated that germ cells produced anomalous MGA that functions against the construction of PRC1.6 as a dominant negative regulator via germ cell-specific alternative splicing for promoting progression of meiosis.

Academic Significance and Societal Importance of the Research Achievements

Mgaの下流標的遺伝子や、MgaによるPRC1.6制御機構が明らかになったことによって、配偶子形成や減数分裂開始における分子メカニズムの解明の大きな一歩となった。また、Mgaは多種多様ながんで変異が報告されており、今回の研究で見つかった知見はMga変異型のがんの病態解明にもポジティブな波及効果をもたらすと考えられる。

Report

(3 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • Research Products

    (7 results)

All 2021 2020

All Journal Article (3 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (4 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Repression of germline genes by PRC1.6 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing2021

    • Author(s)
      Mochizuki K, Sharif J, Shirane K, Uranishi K, Bogutz AB, Janssen SM, Suzuki A, Okuda A, Koseki H, Lorincz MC.
    • Journal Title

      Nature Communications

      Volume: 12(1) Issue: 1 Pages: 7020-7020

    • DOI

      10.1038/s41467-021-27345-x

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Two DNA binding domains of MGA act in combination to suppress ectopic activation of meiosis-related genes in mouse embryonic stem cells2021

    • Author(s)
      Uranishi K, Hirasaki M, Kitamura Y, Mizuno Y, Nishimoto M, Suzuki A, Okuda A.
    • Journal Title

      Stem Cells

      Volume: 39(11) Issue: 11 Pages: 1435-1446

    • DOI

      10.1002/stem.3433

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification of germ cell-specific Mga variant mRNA that promotes meiosis via impediment of a non-canonical PRC12021

    • Author(s)
      Kitamura Y, Uranishi K, Hirasaki M, Nishimoto M, Suzuki A, Okuda A.
    • Journal Title

      Scientific Reports

      Volume: 11(1) Issue: 1 Pages: 9737-9737

    • DOI

      10.1038/s41598-021-89123-5

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] MgaはbHLHZ領域を介してMeiosin-Stra8シグナルを制御することによっ て減数分裂移行を抑制する2021

    • Author(s)
      浦西洸介 北村友佳 鈴木歩 平崎正孝 西本正純 奥田晶彦
    • Organizer
      第44回分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] MAXによるマウス生殖細胞の減数分裂開始制御機構2021

    • Author(s)
      鈴木歩 浦西洸介 北村友佳 平崎正孝 西本正純 奥田晶彦
    • Organizer
      第44回分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Identification of meiotic germ cell-specific Mga splice variant that functions as a negative regulator of non-canonical PRC1 leading to the promotion of meiotic onset2020

    • Author(s)
      Kitamura Y, Uranishi K, Hirasaki M, Nishimoto M, Suzuki A and Okuda A
    • Organizer
      ISSCR 2020
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Generation of meiotic germ cell-specific Mga splice variant for promoting meiotic onset via inactivation of non-canonical PRC12020

    • Author(s)
      Kitamura Y, Uranishi K, Hirasaki M, Nishimoto M, Suzuki A and Okuda A
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2023-01-30  

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