研究課題/領域番号 |
21K06870
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研究種目 |
基盤研究(C)
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配分区分 | 基金 |
応募区分 | 一般 |
審査区分 |
小区分49010:病態医化学関連
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研究機関 | 熊本大学 |
研究代表者 |
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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研究分担者 |
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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研究期間 (年度) |
2021-04-01 – 2024-03-31
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研究課題ステータス |
交付 (2022年度)
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配分額 *注記 |
4,160千円 (直接経費: 3,200千円、間接経費: 960千円)
2023年度: 1,300千円 (直接経費: 1,000千円、間接経費: 300千円)
2022年度: 1,430千円 (直接経費: 1,100千円、間接経費: 330千円)
2021年度: 1,430千円 (直接経費: 1,100千円、間接経費: 330千円)
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キーワード | Hematopoietic stem cell / Inflammation / Epigenetics / Stress / SETD2 / MYD88 |
研究開始時の研究の概要 |
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.
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研究実績の概要 |
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.
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現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
We have uncovered a critical role of methyltransferase SET Domain Containing 2 (SETD2) in regulating quiescence, proliferation and differentiation of adult HSCs via maintenance of H3K36me3. SETD2’s stability is regulated by an E3 ubiquitin ligase Speckle-type POZ protein (SPOP). Thus, SPOP is likely to be a negative regulator for HSC quiescence, and inhibition of SPOP may maintain HSC quiescence. We also found that hematopoietic stem and progenitor cells (HSPCs), either with Spop- or Setd2-deficiency, share a common transcriptional signature in stress hematopoiesis identified by RNA-seq analysis. Among stress hematopoiesis genes, we found that genes involved in myeloid cells mediated immunity and activation, and cell migration were activated in those KO cells, indicating that the immune signaling pathway was involved in the SPOP-SETD2-H3K36me3 axis to control HSC fitness.
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今後の研究の推進方策 |
To understand how Spop regulated HSC in response to stress conditions, we will clarify whether (1) LPS and Poly (I:C) administration could change H3K36me2 and H3K36me3 levels in Spopflox/flox or Spop KO mouse HSPCs (2) binding between SETD2 and ASH1L could successfully reduce in SPOPY87N expressing HEK293 or K562 cells. Also, we will clarify the methylation level of H3K36me2 and me3. We will attempt to determine whether targeting of SPOP-mediated MYD88-dependent inflammatory activation and H3K36me2/me3 imbalance can maintain HSC stemness.
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