Ectopic expression of DNA methyltransferases DNMT3A2 and DNMT3L leads to aberrant hypermethylation and postnatal lethality in mice

DNA methylation is generally known to inactivate gene expression. The DNA methyltransferases (DNMTs), DNMT3A and DNMT3B, catalyze somatic cell lineage-specific DNA methylation, while DNMT3A and DNMT3L catalyze germ cell lineage-specific DNA methylation. How such lineage- and gene-specific DNA methylation patterns are created remains to be elucidated. To better understand the regulatory mechanisms underlying DNA methylation, we generated transgenic mice that constitutively expressed DNMT3A and DNMT3L, and analyzed DNA methylation, gene expression, and their subsequent impact on ontogeny. All transgenic mice were born normally but died within 20 weeks accompanied with cardiac hypertrophy. Several genes were repressed in the hearts of transgenic mice compared with those in wild-type mice. CpG islands of these downregulated genes were highly methylated in the transgenic mice. This abnormal methylation occurred in the perinatal stage. Conversely, mono-allelic DNA methylation at imprinted loci was faithfully maintained in all transgenic mice, except H19. Thus, the loci preferred by DNMT3A and DNMT3L differ between somatic and germ cell lineages. We generated transgenic mice expressing both DNMT3A2 and DNMT3L ectopically in broad somatic cells throughout the lifetime (DNMTs-Tg mice). All DNMTs-Tg mice showed delayed postnatal growth and finally died within 20 weeks after birth. We hypothesized that the exogenous DNMT3A2 and DNMT3L abnormally methylated some genes to produce these severe phenotypes. As DNA methylation generally silences gene expression, we conducted comprehensive gene expression analyses in heart tissues of DNMTs-Tg mice to identify genes that were abnormally hypermethylated by exogenous DNMT3A2 and DNMT3L.