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. 2025 Aug 7;32(8):1251-1266.e8.
doi: 10.1016/j.stem.2025.06.010. Epub 2025 Jul 17.

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

Infencia Xavier Raj  1 , Won Kyun Koh  1 , Jessica Harrison  2 , Christine R Zhang  1 , Barbara Soares  3 , Roberta Amato  3 , Aishwarya Krishnan  1 , David R O'Leary  1 , Hassan Bjeije  1 , Tyler M Parsons  1 , Wentao Han  1 , Andrew L Young  3 , Ting Wang  2 , Luis F Z Batista  3 , Grant A Challen  4
Affiliations

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

Infencia Xavier Raj et al. Cell Stem Cell. .

Abstract

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.

Keywords: DNA methylation; DNMT3A; hematopoietic stem cell; telomerase; telomere.

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Conflict of interest statement

Declaration of interests The authors declare the following competing interests (unrelated to this work): T.M.P. has performed consulting for Pillar Patient Advocates, Silence Therapeutics, and the MPNRF. A.L.Y. has performed consulting for BioGenerator and is a co-founder, CEO, and shareholder of Pairidex, Inc. L.F.Z.B. has received research funding from Enanta Pharma. G.A.C. has performed consulting and received research funding from Incyte, Ajax Therapeutics, and ReNAgade Therapeutics Management, and is a co-founder, member of the scientific advisory board, and shareholder of Pairidex, Inc.

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