Novakovic, B.;
Sibson, M.;
Ng, H.K.;
Manuelpillai, U.;
Rakyan, V.;
Down, T.;
Beck, S.;
... Saffery, R.; + view all
(2009)
Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface.
Journal of Biological Chemistry
, 284
(22)
pp. 14838-14848.
10.1074/jbc.M809542200.
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Abstract
Plasma concentrations of biologically active vitamin D (1,25- (OH)2D) are tightly controlled via feedback regulation of renal 1-hydroxylase (CYP27B1; positive) and 24-hydroxylase (CYP24A1; catabolic) enzymes. In pregnancy, this regulation is uncoupled, and 1,25-(OH)2D levels are significantly elevated, suggesting a role in pregnancy progression. Epigenetic regulation of CYP27B1 and CYP24A1 has previously been described in cell and animal models, and despite emerging evidence for a critical role of epigenetics in placentation generally, little is known about the regulation of enzymes modulating vitamin D homeostasis at the fetomaternal interface. In this study, we investigated the methylation status of genes regulating vitamin D bioavailability and activity in the placenta. No methylation of the VDR (vitamin D receptor) and CYP27B1 genes was found in any placental tissues. In contrast, the CYP24A1 gene is methylated in human placenta, purified cytotrophoblasts, and primary and cultured chorionic villus sampling tissue. No methylation was detected in any somatic human tissue tested. Methylation was also evident in marmoset and mouse placental tissue. All three genes were hypermethylated in choriocarcinoma cell lines, highlighting the role of vitaminDderegulation in this cancer. Gene expression analysis confirmed a reduced capacity for CYP24A1 induction with promoter methylation in primary cells and in vitro reporter analysis demonstrated that promoter methylation directly down-regulates basal promoter activity and abolishes vitamin D-mediated feedback activation. This study strongly suggests that epigenetic decoupling of vitamin D feedback catabolism plays an important role in maximizing active vitamin D bioavailability at the fetomaternal interface.
Type: | Article |
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Title: | Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1074/jbc.M809542200 |
Publisher version: | http://dx.doi.org/10.1074/jbc.M809542200 |
Language: | English |
Additional information: | This research was originally published in Journal of Biological Chemistry. Novakovic, B. and Sibson, M. and Ng, H.K. and Manuelpillai, U. and Rakyan, V. and Down, T. and Beck, S. and Fournier, T. and Evain-Brion, D. and Dimitriadis, E. and Craig, J.M. and Morley, R. and Saffery, R. Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface. Journal of Biological Chemistry. 2009; 284 (22). pp.14838-14848. © the American Society for Biochemistry and Molecular Biology. |
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/20074 |
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