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

Boris Novakovic, Nicholas Wong, Mandy Sibson, Hong Ng, Ruth Morley, Ursula Manuelpillai, Thomas Down, Vardhman Rakyan, Stephan Beck, Stefan Hiendleder, Claire Roberts, Jeffrey Craig, Richard Saffery

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)9583 - 9593
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number13
DOIs
Publication statusPublished - 2010

Cite this

Novakovic, Boris ; Wong, Nicholas ; Sibson, Mandy ; Ng, Hong ; Morley, Ruth ; Manuelpillai, Ursula ; Down, Thomas ; Rakyan, Vardhman ; Beck, Stephan ; Hiendleder, Stefan ; Roberts, Claire ; Craig, Jeffrey ; Saffery, Richard. / DNA methylation-mediated down-regulation of DNA methyltransferase-1 (DNMT1) is coincident with, but not essential for, global hypomethylation in human placenta. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 13. pp. 9583 - 9593.
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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.",
author = "Boris Novakovic and Nicholas Wong and Mandy Sibson and Hong Ng and Ruth Morley and Ursula Manuelpillai and Thomas Down and Vardhman Rakyan and Stephan Beck and Stefan Hiendleder and Claire Roberts and Jeffrey Craig and Richard Saffery",
year = "2010",
doi = "10.1074/jbc.M109.064956",
language = "English",
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pages = "9583 -- 9593",
journal = "Journal of Biological Chemistry",
issn = "1083-351X",
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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 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, vol. 285, no. 13, pp. 9583 - 9593. https://doi.org/10.1074/jbc.M109.064956

DNA methylation-mediated down-regulation of DNA methyltransferase-1 (DNMT1) is coincident with, but not essential for, global hypomethylation in human placenta. / Novakovic, Boris; Wong, Nicholas; Sibson, Mandy; Ng, Hong; Morley, Ruth; Manuelpillai, Ursula; Down, Thomas; Rakyan, Vardhman; Beck, Stephan; Hiendleder, Stefan; Roberts, Claire; Craig, Jeffrey; Saffery, Richard.

In: Journal of Biological Chemistry, Vol. 285, No. 13, 2010, p. 9583 - 9593.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - DNA methylation-mediated down-regulation of DNA methyltransferase-1 (DNMT1) is coincident with, but not essential for, global hypomethylation in human placenta

AU - Novakovic, Boris

AU - Wong, Nicholas

AU - Sibson, Mandy

AU - Ng, Hong

AU - Morley, Ruth

AU - Manuelpillai, Ursula

AU - Down, Thomas

AU - Rakyan, Vardhman

AU - Beck, Stephan

AU - Hiendleder, Stefan

AU - Roberts, Claire

AU - Craig, Jeffrey

AU - Saffery, Richard

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/20071334

U2 - 10.1074/jbc.M109.064956

DO - 10.1074/jbc.M109.064956

M3 - Article

VL - 285

SP - 9583

EP - 9593

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 13

ER -