Non-canonical functions of DNMT3A in hematopoietic stem cells regulate telomerase activity and genome integrity

Grant Challen, PhD, Professor, WashU Medicine Division of Oncology, teamed up with  Luis F. Z. Batista, PhD, Associate Professor and Andrew L. Young, MD, PhD, Assistant Professor, WashU Medicine Division of Hematology, on a new research publication “Non-canonical functions of DNMT3A in hematopoietic stem cells regulate telomerase activity and genome integrity”, published this month in Cell Stem Cell.

DNMT3A is a  central regulator of blood stem cells (hematopoietic stem cells, or HSCs), and it’s one of the most frequently mutated genes in clonal hematopoiesis. Traditionally, DNMT3A is known for its job as a DNA methyltransferase, but the team was wondering: could DNMT3A have other jobs outside of DNA methylation?

Using different models of impaired DNMT3A, they show that hematopoietic stem cells missing this enzyme  thrive and bypass the usual limits on how many times they can divide. The secret? They ramp up telomerase activity and keep their telomeres long, helping them maintain their replicative lifespan. This work uncovers a new side of DNMT3A, one that regulates stem cell longevity and genome stability in ways that had not yet been described, and that may help explain how DNMT3A mutations contribute to disease.Using different models of impaired DNMT3A, they show that hematopoietic stem cells missing this enzyme  thrive and bypass the usual limits on how many times they can divide. The secret? They ramp up telomerase activity and keep their telomeres long, helping them maintain their replicative lifespan. This work uncovers a new side of DNMT3A, one that regulates stem cell longevity and genome stability in ways that had not yet been described, and that may help explain how DNMT3A mutations contribute to disease.