Dnmt3a, a de novo DNA methyltransferase, is crucial for genome regulation and development. DNA methylation by Dnmt3a at cytosines is essential for various processes, and its dysregulation is implicated in diseases like cancer [1,3]. It has non-overlapping functions with Dnmt3b in development, and together they are required for de novo methylation in ES cells and early embryos [3].

In mouse models, Dnmt3a -/- HSCs show substantial expansion during chronic mycobacterial infection, indicating that IFNγ signaling induced during chronic infection can drive Dnmt3a-loss-of-function clonal hematopoiesis [2]. In the context of leukemia, Dnmt3a mutations are early events, conferring poor prognosis to acute myeloid leukemia (AML) patients. For example, the R882H mutation in Dnmt3a causes high expression of NAMPT through DNA hypomethylation, leading to abnormal NAM-NAD metabolism, accelerated cell cycle progression, and promoting leukemia development [4,5].

In conclusion, Dnmt3a is essential for de novo DNA methylation and normal development. Studies using gene-knockout mouse models have revealed its role in disease conditions such as clonal hematopoiesis and leukemia, highlighting its significance in understanding disease mechanisms and potentially developing targeted therapies.

References:

1. Zhang, Zhi-Min, Lu, Rui, Wang, Pengcheng, Wang, Gang Greg, Song, Jikui. 2018. Structural basis for DNMT3A-mediated de novo DNA methylation. In Nature, 554, 387-391. doi:10.1038/nature25477. https://pubmed.ncbi.nlm.nih.gov/29414941/

2. Hormaechea-Agulla, Daniel, Matatall, Katie A, Le, Duy T, Kimmel, Marek, King, Katherine Y. 2021. Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling. In Cell stem cell, 28, 1428-1442.e6. doi:10.1016/j.stem.2021.03.002. https://pubmed.ncbi.nlm.nih.gov/33743191/

3. Okano, M, Bell, D W, Haber, D A, Li, E. . DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. In Cell, 99, 247-57. doi:. https://pubmed.ncbi.nlm.nih.gov/10555141/

4. Yang, Xuejiao, Wang, Xiao, Yang, Ying, Shang, Siqi, Wang, Yueying. 2023. DNMT3A mutation promotes leukemia development through NAM-NAD metabolic reprogramming. In Journal of translational medicine, 21, 481. doi:10.1186/s12967-023-04323-z. https://pubmed.ncbi.nlm.nih.gov/37464424/

5. Khrabrova, Dariya A, Yakubovskaya, Marianna G, Gromova, Elizaveta S. . AML-Associated Mutations in DNA Methyltransferase DNMT3A. In Biochemistry. Biokhimiia, 86, 307-318. doi:10.1134/S000629792103007X. https://pubmed.ncbi.nlm.nih.gov/33838631/