<< Back to MOTIFvations Blog Home Page

Above and Beyond DNA Methylation: A Non-Canonical Role for Dnmt3a Described in Hematopoietic Stem Cells

By Stuart P. Atkinson, Ph.D.

November 24, 2025

Tweet

The Enigmatic Role of Dnmt3a in Hematopoietic Stem Cells

The de novo DNA methyltransferase 3 alpha (DNMT3A) - a critical regulator of hematopoietic stem cell (HSC) fate decisions (Challen et al., 2011 and Challen et al., 2014) - represents the most recurrently mutated gene observed in cases of human clonal hematopoiesis (Challen & Goodell), which can lead to the development of blood cancers such as myelodysplastic syndrome, acute myeloid leukemia, and T cell acute lymphoblastic leukemia.

While we generally recognize DNMT3A in the realm of epigenetics as a DNA methyltransferase enzyme (Okano, Xie, & Li), HSCs lacking DNMT3A activity display only modest alterations to DNA methylation patterns, which do not correlate with downstream gene expression changes or worsen over time (Challen et al., 2011, Challen et al., 2014, Jeong et al., and Spencer et al.). DNA methylation plays a crucial role in regulating gene expression, and recent research has underscored the significance of this epigenetic regulatory layer as a biomarker for cancer, aging, and various other human diseases. While the maintenance methyltransferase DNMT1 copies DNA methylation patterns to daughter strands during DNA replication, DNMT3a and DNMT3b (with the help of DNMT3L) represent de novo methyltransferases that establish DNA methylation patterns during development. However, as noted above, the intriguing findings of numerous studies have raised questions regarding the relevance of DNMT3A-mediated DNA methylation in regulating HSC fate decisions.

Researchers from the laboratory of Grant A. Challen (Washington University) developed a series of mice expressing forms of Dnmt3a that lack DNA methylation ability to explore possible DNA-methylation-independent, non-canonical functions of Dnmt3a in HSCs (Raj, Koh, Harrison, Zhang et al.). Excitingly, their new Cell Stem Cell study now reveals a non-canonical, DNA-methylation-independent role for Dnmt3a in regulating HSC longevity via telomere maintenance and increased genomic stability. Does this new HSC-based study take Dnmt3a above the epigenetic dominion of DNA methylation and beyond toward the realm of non-canonical roles?

 Back to Table of Contents

A Non-canonical Role for Dnmt3A Above and Beyond DNA Methylation

In brief, the authors of this fascinating new study compared mouse models with HSCs expressing wild-type Dnmt3a with those lacking Dnmt3 entirely and those containing a version of Dnmt3a that lacked DNA methyltransferase activity.

Wild-type mice displayed an appropriate balance of HSC self-renewal and differentiation to support the normal function of the blood system. However, analysis of mice with complete Dnmt3a loss revealed that they suffered from the clonal expansion of HSCs and a lack of HSC differentiation into mature blood cells; furthermore, Dnmt3-null HSCs possessed the ability to undergo indefinite transplantation (which normal HSCs can only support for a short time) supported by increased telomerase activity, the maintenance of telomere length, and improved genome stability. The shortening of telomeres - repetitive DNA sequences that cap chromosomal ends – that occurs upon each cell division eventually leads to DNA damage signaling events that prompt cell senescence and the loss of cell function (Griffith et al.). In HSCs, previous studies had revealed that telomere shortening reduced HSC functionality (Colla et al.). Here, this clonal expansion of HSCs in the absence of Dnmt3a could allow for the formation of the various blood cancers noted above. Finally, and perhaps most interestingly, mice with HSCs expressing a Dnmt3a form that lacked DNA methyltransferase activity displayed an HSC self-renewal/differentiation capacity and telomere size similar to those of wild-type HSCs.

Overall, this study provides evidence that the differentiation of wild-type HSCs requires the DNA methylation function of Dnmt3a; however, Dnmt3a also plays an additional non-canonical role unrelated to DNA methylation that regulates their self-renewal and overall longevity.

 Back to Table of Contents

Going Above and Beyond to Explore the Non-canonical Roles of Dnmt3a

Overall, these exciting findings provide robust evidence for a non-canonical function of Dnmt3a in HSCs related to the regulation of telomere length maintenance and genome stability, in addition to the canonical, DNA methylation-associated function that supports HSC differentiation. The authors do finally note a need for further studies to definitively conclude this exciting link; these may include the clarification of the mechanisms controlling telomere lengthening in HSCs in short- and long-term expansion times, the exploration of additional levels of regulation in HSCs impacted by Dnmt3a, and a need to overcome the vanishingly small number of cells commonly available for analysis.

Active Motif can help move your epigenetics research forward, whether it is related to Dnmt3a, DNA methyltransferases, DNA methylation, or beyond!

 Back to Table of Contents

About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

Contact Stuart on X with any questions

Related Articles

<< Back to MOTIFvations Blog Home Page