The genome of extraembryonic tissue, such as the placenta, is hypomethylated 
relative to that in somatic tissues. However, the origin and role of this 
hypomethylation remains unclear. The DNA methyltransferases DNMT1, -3A, and -3B 
are the primary mediators of the establishment and maintenance of DNA 
methylation in mammals. In this study, we investigated promoter 
methylation-mediated epigenetic down-regulation of DNMT genes as a potential 
regulator of global methylation levels in placental tissue. Although DNMT3A and 
-3B promoters lack methylation in all somatic and extraembryonic tissues tested, 
we found specific hypermethylation of the maintenance DNA methyltransferase 
(DNMT1) gene and found hypomethylation of the DNMT3L gene in full term and first 
trimester placental tissues. Bisulfite DNA sequencing revealed monoallelic 
methylation of DNMT1, with no evidence of imprinting (parent of origin effect). 
In vitro reporter experiments confirmed that DNMT1 promoter methylation 
attenuates transcriptional activity in trophoblast cells. However, global 
hypomethylation in the absence of DNMT1 down-regulation is apparent in 
non-primate placentas and in vitro derived human cytotrophoblast stem cells, 
suggesting that DNMT1 down-regulation is not an absolute requirement for genomic 
hypomethylation in all instances. These data represent the first demonstration 
of methylation-mediated regulation of the DNMT1 gene in any system and 
demonstrate that the unique epigenome of the human placenta includes 
down-regulation of DNMT1 with concomitant hypomethylation of the DNMT3L gene. 
This strongly implicates epigenetic regulation of the DNMT gene family in the 
establishment of the unique epigenetic profile of extraembryonic tissue in 
humans.