Longevity & AgingDNMT3A Regulates Stem Cell Lifespan via Telomerase, Not Just DNA Methylation
DNMT3A is the most commonly mutated gene in age-related clonal hematopoiesis, long assumed to drive stem cell expansion by altering DNA methylation. This study challenges that assumption. Using engineered mice with DNMT3A proteins that lack methylation capacity, researchers found that the self-renewal advantage of DNMT3A-null blood stem cells persists even when methylation activity is abolished — pointing to non-canonical functions. Crucially, DNMT3A-null stem cells showed elevated telomerase activity and maintained telomere length across indefinite serial transplantation, whereas normal stem cells exhausted. This identifies DNMT3A as an unexpected regulator of telomere biology and stem cell longevity, with implications for understanding clonal hematopoiesis and hematologic malignancy.
