Dnmt3l, a member of the DNMT3 family, has no DNA methyltransferase activity but is crucial for regulating de novo DNA methylation. It integrates DNA methylation and histone modification-based epigenetic circuits, and is involved in various biological processes such as neural development, stem cell regulation, and germ cell DNA methylation [2,3,5]. Genetic models like KO or CKO mouse models are valuable for studying its functions.

In Dnmt3l-deficient mouse embryonic stem cells (mESCs), there is down-regulation of DNMT3A, especially DNMT3A2, leading to hypomethylation at many DNMT3A target regions, indicating Dnmt3l is a positive regulator of DNA methylation as it maintains DNMT3A stability [2].

In Dnmt3l conditional knockin mice, overexpression of Dnmt3l promotes neural differentiation by enhancing STAT1 and STAT3 phosphorylation independent of DNA methylation [1].

In postnatal testes, Dnmt3l-KO in THY1(+) spermatogonial stem/progenitor cells (SPCs) leads to reduced promyelocytic leukemia zinc finger (PLZF) stability, over-activation of ERK and AKT signaling cascades, and premature stem cell exhaustion, suggesting Dnmt3l is required to balance SPC cycling and quiescence [4].

Also, using Dnmt3l-knockout donor cells in combination with Trichostatin A treatment improves the developmental efficiency and quality of cloned embryos, with Dnmt3l-KO donor cells offering a more permissive epigenetic state for nuclear transfer reprogramming [6].

In conclusion, Dnmt3l plays essential roles in DNA methylation, neural differentiation, and stem cell fate determination. Studies using KO/CKO mouse models have revealed its significance in diseases like Down syndrome-related abnormal neurodevelopment, highlighting its potential as a therapeutic target for understanding and treating such conditions [1,7].