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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

Novakovic, B.; Wong, N. C.; Sibson, M.; Ng, H.-K.; Morley, R.; Manuelpillai, U.; Down, T.; ... Saffery, R.; + view all (2010) DNA methylation-mediated down-regulation of DNA methyltransferase-1 (DNMT1) is coincident with, but not essential for, global hypomethylation in human placenta. Journal of Biological Chemistry , 285 (13) pp. 9583-9593. 10.1074/jbc.M109.064956. Green open access

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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.

Type: Article
Title: DNA methylation-mediated down-regulation of DNA methyltransferase-1 (DNMT1) is coincident with, but not essential for, global hypomethylation in human placenta
Open access status: An open access version is available from UCL Discovery
DOI: 10.1074/jbc.M109.064956
Publisher version: http://dx.doi.org/10.1074/jbc.M109.064956
Language: English
Additional information: This research was originally published in Journal of Biological Chemistry. Novakovic, B. and Wong, N. C. and Sibson, M. and Ng, H.-K. and Morley, R. and Manuelpillai, U. and Down, T. and Rakyan, V. K. and Beck, S. and Hiendleder, S. and Roberts, C. T. and Craig, J. M. and Saffery, R. DNA methylation-mediated down-regulation of DNA methyltransferase-1 (DNMT1) is coincident with, but not essential for, global hypomethylation in human placenta. Journal of Biological Chemistry. 2010; 285 (13). pp. 9583-9593. © the American Society for Biochemistry and Molecular Biology.
Keywords: Development differentiation/tissue, DNA/methylation, DNA/methyltransferase, epigenetics, gene transcription, extraembryonic tissue, placenta, trophoblast
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/19491
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