2022 Fiscal Year Research-status 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 / Inflammation / Epigenetics |
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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 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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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
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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| Strategy for Future Research Activity |
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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| Causes of Carryover |
昨年度の研究の進捗によって、若干使用額が少なくなったが、今年度は費用のかかるオミックス解析などを予定しており、その為に使用される。
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