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DNA methylation-mediated down-regulation of DNA methyltransferase-1 (DNMT1) is coincident with, but not essential for, global hypomethylation in human placenta

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journal contribution
posted on 2010-03-26, 00:00 authored by Boris Novakovic, Nick C Wong, Mandy Sibson, Hong-Kiat Ng, Ruth Morley, Ursula Manuelpillai, Thomas Down, Vardhman K Rakyan, Stephan Beck, Stefan Hiendleder, Claire T Roberts, Jeffrey CraigJeffrey Craig, Richard Saffery
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.

History

Journal

Journal of biological chemistry

Volume

285

Pagination

9583-9593

Location

Rockville, Md.

Open access

  • Yes

eISSN

1083-351X

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

2010, The American Society for Biochemistry and Molecular Biology, Inc.

Issue

13

Publisher

American Society for Biochemistry and Molecular Biology