Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/59928
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Type: Journal article
Title: DNA methylation-mediated Down-regulation of DNA methyltransferase-1 (DNMT1) is coincident with, but not essential for, global hypomethylation in human placenta
Author: Novakovic, B.
Wong, N.
Sibson, M.
Ng, H.
Morley, R.
Manuelpillai, U.
Down, T.
Rakyan, V.
Beck, S.
Hiendleder, S.
Roberts, C.
Craig, J.
Saffery, R.
Citation: Journal of Biological Chemistry, 2010; 285(13):9583-9593
Publisher: Amer Soc Biochemistry Molecular Biology Inc
Issue Date: 2010
ISSN: 0021-9258
1083-351X
Statement of
Responsibility: 
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 M. Craig, and Richard Saffery
Abstract: 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.
Keywords: Stem Cells; Trophoblasts; Placenta; Humans; DNA (Cytosine-5-)-Methyltransferase; Sequence Analysis, DNA; Cell Differentiation; DNA Methylation; Down-Regulation; Epigenesis, Genetic; Gene Expression Regulation, Enzymologic; Base Sequence; Pregnancy; Molecular Sequence Data; Female
Rights: © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
RMID: 0020096227
DOI: 10.1074/jbc.M109.064956
Appears in Collections:Obstetrics and Gynaecology publications

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