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

Abstract

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, monoallelic 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.

The Role of Clonal Hematopoiesis of Indeterminant Potential and DNA (Cytosine-5)-Methyltransferase Dysregulation in Pulmonary Arterial Hypertension and Other Cardiovascular Diseases

“…Sasaki et al established a Vasa-Cre-driven transgenic mouse model that constitutively expressed DNMT3A and DNMT3L ectopically after fertilization [153]. Both of these enzymes are important for germline-specific DNA methylation [153].…”

“…Sasaki et al established a Vasa-Cre-driven transgenic mouse model that constitutively expressed DNMT3A and DNMT3L ectopically after fertilization [153]. Both of these enzymes are important for germline-specific DNA methylation [153]. They found that all mice were born without complications, but died within 20 weeks due to cardiac failure [153].…”

“…Both of these enzymes are important for germline-specific DNA methylation [153]. They found that all mice were born without complications, but died within 20 weeks due to cardiac failure [153]. In total, 549 genes were downregulated in their heart cells due to perinatal hypermethylation [153].…”

“…They found that all mice were born without complications, but died within 20 weeks due to cardiac failure [153]. In total, 549 genes were downregulated in their heart cells due to perinatal hypermethylation [153]. It is evident that DNMTs are important in proper cardiovascular development, and future research should further investigate their role in CHDs and paediatric CVD.…”

DNA methylation regulated by ascorbic acids in yak preimplantation embryo helps to improve blastocyst quality

“…DNA methylation was catalyzed by the DNA methyltransferases family, which comprises three members: DNMT1, DNMT3a, and DNMT3b (Vassena, Dee Schramm, & Latham, ). The de novo methyltransferases DNMT3a and DNMT3b are mainly responsible for the establishment of new DNA methylation patterns, and the other family member DNMT1, called the maintenance methyltransferases, plays a significant role in maintaining the 5mC pattern through DNA replication (Sasaki et al, ). A previous report has shown that DNA demethylation and remethylation are typical methylation pattern during embryo development (Deshmukh et al, ).…”