A Dnmt1 knock-out mouse for epigenetic studies
(A) Side (top) and dorsal (bottom) view of Dnmt1ps mutant embryos at E9.5. (B-D) Cytological epigenetic defects in Dnmt1ps mutant cell nuclei. (B) Global loss of 5-methylcytosine (5mC). (C) Decrease of HP1β association at heterochromatic regions intensely stained by DAPI. (D) Loss of hemi-methylated CpG-dependent DNMT1 localization at replication foci (PCNA).
Epigenetic changes are defined as modifications that induce heritable changes in gene expression without changes in the DNA sequence. The methylation of cytosine on the 5-carbon position is a heritable epigenetic DNA modification that affects mammalian development. Three DNA methyltransferases, DNMT1, DNMT3A, and DNMT3B, are coordinately expressed and play an important role in the regulation of gene expression, genomic imprinting, and embryogenesis. 129;B6-Dnmt1tm1Okan mice (Acc. No. CDB0500K, RBRC04774) were generated to examine the roles of the catalytic activity of DNMT1 in vivo by creating a Dnmt1psallele that expresses a protein with a point mutation (DNMT1-C1229S) that lacks catalytic activity. Homozygous Dnmt1psmutant mice exhibit developmental arrest, accompanied by multiple defects, shortly after gastrulation. The phenotypic similarity of the homozygous Dnmt1psmutant mice with DNMT1-null mutant (Dnmt1c) mice clearly indicates that the catalytic activity of DNMT1 is essential for mammalian development. The 129;B6-Dnmt1tm1Okan mice together with other Dnmt knock-out mice are invaluable strains to study the role of these methyltransferases in mammalian epigenetics.