2023 Fiscal Year Annual Research Report
A Crosstalk Between Inflammation and Epigenetics in Regulating HSC Fitness
| Project/Area Number |
21K06870
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| Research Institution | Kumamoto University |
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Principal Investigator |
HUANG Gang 熊本大学, 国際先端医学研究機構, 客員教授 (30836367)
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| 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)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | Hematopoietic stem cell / MYD88 / TLR / SETD2 |
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| Outline of Annual 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 will examine whether “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 aim to determine: (1) In steady state, cytoplasmic SPOP triggers MYD88 degradation to decrease ASH1L-mediated H3K36me2 and prevent HSCs from proliferation and differentiation; (2) In response to inflammation, SPOP dissociates from MYD88, translocates into the nucleus and subsequently degrades SETD2 to reduce H3K36me3 and promote proliferation and differentiation of HSCs. Targeting of SPOP-mediated MYD88-dependent inflammatory activation and H3K36me2/me3 imbalance can maintain HSC stemness.
Our study provide a deeper understanding of HSC homeostasis regulated through the crosstalk between inflammation and epigenetic regulations. By targeting of the key HSC regulators identified from this project, it will provide new therapeutic strategy for preventing HSCs from exhaustion by inactivation of MYD88-dependent inflammatory activation and restoration of H3K36me2/me3 balance.
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