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A Crosstalk Between Inflammation and Epigenetics in Regulating HSC Fitness

Research Project

Project/Area Number 21K06870
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49010:Pathological biochemistry-related
Research InstitutionKumamoto University

Principal Investigator

Huang Gang  熊本大学, 国際先端医学研究機構, 客員教授 (30836367)

Co-Investigator(Kenkyū-buntansha) 指田 吾郎  熊本大学, 国際先端医学研究機構, 特別招聘教授 (70349447)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsHematopoietic stem cells / Inflammation / Toll-like receptor / Transformation / Regeneration / Histone methylation / Hematopoietic stem cell / MYD88 / TLR / SETD2 / Epigenetics / Stress
Outline of Research at the Start

The functionality of hematopoietic stem cell (HSC) compartment hinges on the limited reversible balance between quiescence and activation. The identity of cell-intrinsic mechanisms required to terminate activation and re-enter dormancy, and the signaling pathways that mediate this transition, remain unresolved key questions. Based on our data, we propose that“A crosstalk between inflammation and epigenetics controls HSC fitness”through nucleocytoplasmic shuttling of an E3 ubiquitin ligase Speckle-type POZ protein (SPOP) functioning in MYD88 or SETD2 degradation.

Outline of Final Research Achievements

The functionality of hematopoietic stem cell (HSC) compartment hinges on the limited reversible balance between quiescence and activation. The identity of cell-intrinsic mechanisms required to terminate activation and re-enter dormancy, and the signaling pathways that mediate this transition, remain unresolved key questions. Based on our data, we have proposed that A crosstalk between inflammation and epigenetics controls HSC fitness through nucleocytoplasmic shuttling of an E3 ubiquitin ligase Speckle-type POZ protein (SPOP) functioning in MYD88 or SETD2 degradation. We observed: (1) In steady state, cytoplasmic SPOP drove MYD88 degradation to decrease H3K36me2 and prevent HSC exhaustion; (2) In response to inflammation, SPOP translocated into the nucleus and subsequently degraded SETD2 to promote expansion of HSC.

Academic Significance and Societal Importance of the Research Achievements

Our study has provided a deeper understanding of HSC homeostasis via the crosstalk between inflammation and epigenetic regulations. It should be able provide new therapeutic strategy for preventing HSCs from exhaustion by inactivation of MYD88-dependent inflammatory activation in the future.

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (7 results)

All 2023 2021 Other

All Int'l Joint Research (3 results) Journal Article (2 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (2 results) (of which Int'l Joint Research: 2 results)

  • [Int'l Joint Research] テキサス大学サンアントニオ健康科学センター/シンシナティ小児病院(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] UTヘルスサンアントニオ(米国)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] シンシナティ小児病院/テキサス大学サンアントニオ(米国)

    • Related Report
      2021 Research-status Report
  • [Journal Article] Runx1/3-driven adaptive endoplasmic reticulum stress pathways contribute to neurofibromagenesis2023

    • Author(s)
      Na Youjin、Hall Ashley、Yu Yanan、Hu Liang、Choi Kwangmin、Burgard Jake A.、Szabo Sara、Huang Gang、Ratner Nancy、Wu Jianqiang
    • Journal Title

      Oncogene

      Volume: 42 Pages: 1038-1047

    • DOI

      10.1038/s41388-023-02620-x

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Exposure to microbial products followed by loss of Tet2 promotes myelodysplastic syndrome via remodeling HSCs2023

    • Author(s)
      Yokomizo-Nakano T, Hamashima A, Kubota S, Bai J, Sorin S, Sun Y, Kikuchi K, Iimori M, Morii M, Kanai A, Iwama A, Huang G, Kurotaki D, Takizawa H, Matsui H, Sashida G.
    • Journal Title

      Journal of Experimental Medicine (JEM)

      Volume: 220 (7) Issue: 7 Pages: 9999-9999

    • DOI

      10.1084/jem.20220962

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Downregulation of Mitochondrial Complex II (MC II) in Myelodysplastic Syndromes2023

    • Author(s)
      Maiko Sezaki, Michihiro Hashimoto, Asumi Yokota, Nathan Salomonis, Leighton Grimes, Gang Huang
    • Organizer
      65th ASH Annual Meeting & Exposition
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] HMGA2 maintains hematopoietic stem cell via pleiotropic regulation of the transcription in stress conditions2021

    • Author(s)
      Sho Kubota, Yuqi Sun, Jie Bai, Takako Yokomizo-Nakano, Mariko Morii, Takako Ideue, Motomi Osato, Terumasa Umemoto, Kimi Araki, Goro Sashida
    • Organizer
      63rd ASH Annual Meeting and Exposition(国際学会)
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research

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Published: 2021-04-28   Modified: 2025-01-30  

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