A Crosstalk Between Inflammation and Epigenetics in Regulating HSC Fitness

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06870
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Kumamoto 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
• Keywords: Hematopoietic stem cells / Inflammation / Toll-like receptor / Transformation / Regeneration / Histone methylation

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.

Free Research Field

血液内科学

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.