Dnmt3l, short for DNA methyltransferase 3-like, is a member of the DNMT3 family. It lacks DNA methyltransferase activity but is crucial in regulating de novo DNA methylation, integrating DNA methylation and histone modification-based epigenetic circuits [2,6]. It is involved in multiple biological processes, including germ cell development, neural differentiation, and stem cell quiescence, and is associated with various diseases such as prion disease, Down syndrome, and hepatocellular carcinoma [1,3,4]. Genetic models, especially KO mouse models, have been valuable in studying its functions.

In KO mouse models, Dnmt3l-deficient mouse embryonic stem cells (mESCs) show down-regulation of DNMT3A, especially DNMT3A2, leading to hypomethylation at many DNMT3A target regions, indicating its role in maintaining DNMT3A stability and positively regulating DNA methylation [2]. In Dnmt3l KO THY1(+) spermatogonial stem/progenitor cells (SPCs), reduced PLZF levels release its antagonist SALL4A, activating ERK and AKT signaling cascades, suggesting Dnmt3l is required to balance SPC cycling and quiescence [5]. Also, Dnmt3l-knockout donor cells combined with Trichostatin A treatment improve the developmental efficiency and quality of cloned embryos, as Dnmt3l-KO mouse embryonic fibroblasts have a more permissive epigenetic state beneficial for NT reprogramming [7].

In conclusion, Dnmt3l plays essential roles in DNA methylation-related biological processes such as maintaining DNMT3A stability, regulating stem cell quiescence, and influencing embryo development. Studies using KO mouse models have enhanced our understanding of its functions in these processes and provided insights into diseases like prion disease, Down syndrome, and hepatocellular carcinoma, potentially offering new strategies for disease treatment and prevention.