2021 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 |
Hematopoietic stem cells (HSCs) sustain hematopoiesis throughout our entire lives. HSCs exit dormancy to restore homeostasis in response to stresses, such as acute inflammation, and must return to a quiescent state to maintain the HSCs' pool. 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. 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.
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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 (Zhou Y, Haematologica 2018). Importantly, SETD2’s stability is regulated by an E3 ubiquitin ligase Speckle-type POZ protein (SPOP) (Zhu K, Nucleic Acids Res. 2017). Thus, SPOP is likely to be a negative regulator for HSC quiescence, and inhibition of SPOP may maintain HSC quiescence. Additionally, hematopoietic stem and progenitor cells (HSPCs), either with Spop- or Setd2-deficiency, share a common transcriptional signature in emergency hematopoiesis identified by RNA-seq analysis. Within these genes, we found that the common enrichment of upregulated genes in myeloid cells mediated immunity and activation, and cell migration, indicating that a common immune signal pathway is involved in the SPOP-SETD2-H3K36me3 axis to control HSC fitness.
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| Strategy for Future Research Activity |
We attempt to determine whether (1) 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.
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