2025-09-11 ワシントン大学セントルイス校
<関連情報>
- https://source.washu.edu/2025/09/surprising-new-roles-discovered-for-known-cancer-gene/
- https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(25)00256-5
造血幹細胞におけるDNMT3Aの非典型的な機能がテロメラーゼ活性とゲノム完全性を調節 Non-canonical functions of DNMT3A in hematopoietic stem cells regulate telomerase activity and genome integrity
Infencia Xavier Raj ∙ Won Kyun Koh ∙ Jessica Harrison, ∙ … ∙ Ting Wang ∙ Luis F.Z. Batista ∙ Grant A. Challen
Cell Stem Cell Published:July 17, 2025
DOI:https://doi.org/10.1016/j.stem.2025.06.010
Graphical abstract
Highlights
- Generation of mouse models to study DNA-methylation-independent Dnmt3a functions
- DNA methylation by Dnmt3a is essential for HSC differentiation, but not self-renewal
- Dnmt3a regulates telomerase expression and activity in HSCs
- Dnmt3a integrates DNA damage response signaling in HSCs with telomerase deficiency
Summary
DNMT3A is a critical regulator of hematopoietic stem cell (HSC) fate decisions and the most recurrently mutated gene in human clonal hematopoiesis (CH). DNMT3A is described as a DNA methyltransferase enzyme, but cells with DNMT3A loss of function show minor changes in DNA methylation that do not correlate with altered gene expression. To explore the possibility that Dnmt3a has DNA-methylation-independent functions in HSCs, we created an allelic series of mice with varying levels of DNA-methylation-impaired Dnmt3a. Clonal expansion of Dnmt3a-deficient HSCs was rescued by Dnmt3a proteins lacking DNA methylation capacity, suggesting that Dnmt3a has important non-canonical functions in HSCs. Dnmt3a-null HSCs can be transplanted indefinitely, implying the ability to circumvent mechanisms that limit the replicative lifespan of HSCs, such as telomere shortening. Dnmt3a-null HSCs show increased telomerase activity and sustain telomere length over serial transplantation, revealing a previously unidentified role for DNMT3A mutations in regulating HSC longevity that is unrelated to DNA methylation function.
