Dnmt1 Conditional Knockout mouse models

Maintenance of CpG methylation depends on Dnmt1, the mouse ortholog of human DNMT1, whose catalytic domain is held autoinhibited by CXXC and BAH modules until UHRF1 delivers hemimethylated DNA and ubiquitinates histone H3, while PCNA tethering couples the enzyme to the replication fork. Loss produces genome-wide hypomethylation, retroelement derepression, loss of imprinting, and chromosomal instability, and homozygous deletion is embryonic lethal around E9.5, whereas hypomorphic alleles that reduce activity to a fraction of normal survive and develop thymic lymphoma, demonstrating that graded dosage rather than binary loss drives tumor phenotypes. Design choices follow directly: hypomorphic and conditional alleles address graded hypomethylation and tumor susceptibility, catalytically dead knockins separate methyltransferase output from scaffolding, and knockins supporting hypomethylating agent studies address pharmacology. The de novo enzymes Dnmt3a and Dnmt3b cannot restore maintenance activity, so assume no compensation when interpreting conditional deletion in adult tissues.

Dnmt1 conditional knockout mice carry a floxed allele so you delete function only where Cre is active. The germline allele stays intact until you cross to a tissue specific Cre. Labs reach for this design when a global knockout is lethal, when they need adult onset loss, or when regional redundancy hides a whole body phenotype.