Dnmt3l, also known as DNA methyltransferase 3-like, is a member of the DNMT3 family. It lacks DNA methyltransferase activity but is a crucial regulator of de novo DNA methylation, integrating DNA methylation and histone modification-based epigenetic circuits [1,5]. It is involved in various biological processes such as germ cell development, neural differentiation, and stem cell quiescence [1,2,4].

In mouse embryonic stem cells, Dnmt3l-deficient models show down-regulation of Dnmt3A, especially Dnmt3A2, leading to hypomethylation at many Dnmt3A target regions. This reveals that Dnmt3l is a positive regulator of DNA methylation by maintaining Dnmt3A stability [1]. In Dnmt3l conditional knockin mice, overexpression of Dnmt3l promotes neural differentiation by enhancing STAT1 and STAT3 phosphorylation, independent of DNA methylation [2]. In postnatal spermatogonial progenitor cells, Dnmt3l-knockout mice demonstrate that Dnmt3l is required to balance the cycling and quiescence of spermatogonial stem/progenitor cells (SPCs) [4]. Also, Dnmt3l-knockout donor cells in somatic cell nuclear transfer improve the developmental efficiency and quality of cloned embryos, suggesting Dnmt3l-KO donor cells may offer a more permissive epigenetic state beneficial for reprogramming [6].

In conclusion, Dnmt3l plays essential roles in multiple biological processes mainly through its regulation of DNA methylation and other epigenetic mechanisms. Studies using Dnmt3l KO/CKO mouse models have provided valuable insights into its functions in neural development, germ cell maintenance, and embryo reprogramming, which may contribute to understanding related disease mechanisms such as those in Down syndrome and certain cancers [2,3].