Epigenetics and stress signals in stem cell aging

2018 Fiscal Year Final Research Report

• Project Area: Establishing a new paradigm of the pathogenesis of diseases through the understanding of stem cell aging
• Project/Area Number: 26115002
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo (2018); Chiba University (2014-2017)
• Principal Investigator: Iwama Atsushi 東京大学, 医科学研究所, 教授 (70244126)
• Co-Investigator(Kenkyū-buntansha): 石川 冬木 京都大学, 生命科学研究科, 教授 (30184493)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Keywords: ステムセルエイジング / 造血幹細胞 / 老化

Outline of Final Research Achievements

We analyzed mouse hematopoietic stem cells (HSCs) and found that polycomb repressive complex 2 (PRC2) target genes marked with H3K27me3 moderately reduce H3K27me3 levels at their promoters in aged HSCs, resulting in the activation of PRC2 target gene signature in aged HSCs. Several aging stresses such as infection and myeloablative stresses attenuated the function of PRC2 like aging. In addition, PRC2 insufficiency in mice accelerated the development of age-related myeloid malignancies, such as myelodysplastic syndrome, in concert with driver mutations. These data suggest that a decline in PRC2 activity is associated with HSC aging and age-related clonal HSC disorders. Age-related decline in PRC2 activity could be one of the epigenomic determinants that facilitate expansion of HSC clones with founding driver.

Free Research Field

幹細胞生物学

Academic Significance and Societal Importance of the Research Achievements

われわれのデータは、幹細胞の加齢変化におけるポリコーム機能の低下がdriver変異を獲得した加齢造血幹細胞がクローン拡大する際のエピゲノム要因となっている可能性を示唆しており、造血幹細胞腫瘍発症におけるステムセルエイジングの意義を支持するものである。このような知見は、加齢に伴う個体の老化と疾患が、幹細胞レベルの加齢変化の影響を大きく受けることを示しており、老化を理解する上で新しい観点を提示するものである。