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Elucidation of the mechanism of how androgen receptor regulates downstream target genes in external genitalia during sexual differentiation.

Research Project

Project/Area Number 19K24051
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0906:Surgery related to the biological and sensory functions and related fields
Research InstitutionWakayama Medical University

Principal Investigator

Kajioka Daiki  和歌山県立医科大学, 先端医学研究所, 助教 (40842737)

Project Period (FY) 2019-08-30 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsアンドロゲン / 性差 / 外生殖器 / 遺伝子発現制御 / ヒストン修飾 / エンハンサー / Sp1 / MafB
Outline of Research at the Start

生殖器官の性分化から病態発症・増悪化に至るまでアンドロゲンの関与は多岐にわたるが、その分子制御機構は未解明である。アンドロゲン受容体(AR)は、転写因子として様々な標的遺伝子の発現を巧みに制御する。現在、ARの標的遺伝子として外生殖器の性差形成因子MafBの発現が、GCリッチ領域に結合する転写因子のエピゲノム制御を介して調節されている可能性を見出しつつある。また、次世代シーケンサーによる網羅的遺伝子発現解析から、性分化過程の外生殖器における新規AR標的遺伝子を同定している。本研究では、外生殖器の性差形成過程をモデルとしてエピゲノム制御を介したAR依存性の普遍的遺伝子発現制御機構を解明する。

Outline of Final Research Achievements

Androgen is an essential endocrine factor for establishing sex differences of external genitalia (ExG). This study aims to uncover the mechanisms of how androgen receptor (AR) regulates its target genes expression by using murine embryonic ExG (eExG). Motif enrichment analyses from AR ChIP-seq identified that Sp1 was a collaborative transcriptional factor of AR. Genome-wide distribution analyses of H3K27ac, H3K4me1, and SP1 from ChIP-seq revealed a similar pattern at AR-mediated regulatory elements in both sexes, suggesting that transcriptional competency for AR target genes was conserved in both male and female. Moreover, Sp1 regulates the acetylation of H3K27 at the enhancers of AR target genes in both sexes. Genetic manipulation of MafB and Sp1 regulatory MafB enhancer elements caused incomplete male-type eExG differentiation. These findings provide novel insight into the androgen-dependent regulatory mechanisms underlying sex differentiation for eExG.

Academic Significance and Societal Importance of the Research Achievements

マウス胎仔外生殖器において、アンドロゲンが標的遺伝子の発現を制御するにあたり、Sp1によるヒストン修飾を介した転写制御領域の活性化の重要性が示唆された。さらに、次世代シーケンサーを駆使したゲノムワイドな解析により、本制御機構は雌雄共通に保存されていることを明らかにした。このことは、既存報告されてきた遺伝的背景のメス個体が雄性分化するためのアンドロゲン応答性を獲得している分子基盤である可能性を示唆するものである。このようなホルモン応答性の獲得に対する初期分子制御基盤を明らかにしたことは、尿道下裂などの泌尿生殖系の先天性疾患から前立腺癌などの癌病態までの幅広い理解に繋がると期待される。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (3 results)

All 2021 2020 2019

All Journal Article (2 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (1 results)

  • [Journal Article] Sexual fate of murine external genitalia development: conserved transcriptional competency for male-biased genes in both sexes.2021

    • Author(s)
      Daiki Kajioka, Kentaro Suzuki, Shoko Matsushita, Shinjiro Hino, Tetsuya Sato, Shuji Takada, Kyoichi Isono, Toru Takeo, Mizuki Kajimoto, Naomi Nakagata, Mitsuyoshi Nakao, Mikita Suyama, Tony DeFalco, Shinichi Miyagawa, Gen Yamada
    • Journal Title

      Proc. Natl. Acad. Sci. USA

      Volume: in press

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Hedgehog Signaling for Urogenital Organogenesis and Prostate Cancer: An Implication for the Epithelial?Mesenchyme Interaction (EMI)2019

    • Author(s)
      Hyuga Taiju、Alcantara Mellissa、Kajioka Daiki、Haraguchi Ryuma、Suzuki Kentaro、Miyagawa Shinichi、Kojima Yoshiyuki、Hayashi Yutaro、Yamada Gen
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 1 Pages: 58-58

    • DOI

      10.3390/ijms21010058

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Androgen receptor (AR) transcriptional activities are regulated by Sp1 during sexual differentiation of external genitalia.2020

    • Author(s)
      Daiki Kajioka, Kentaro Suzuki, Shoko Matsushita, Shinjiro Hino, Tetsuya Sato, Shuji Takada, Shinichi Miyagawa, Toru Takeo, Naomi Nakagata, Mikita Suyama, Kyoichi Isono, Mitsuyoshi Nakao and Gen Yamada
    • Organizer
      53rd Annual Meeting of JSDB
    • Related Report
      2019 Research-status Report

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Published: 2019-09-03   Modified: 2022-01-27  

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