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Placenta-specific methylation of the vitamin d 24-hydroxylase gene implications for feedback autoregulation of active vitamin d levels at the fetomaternal interface

Novakovic, B; Sibson, M; Ng, HK; 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. The journal of biological chemistry , 284 (22) 14838 - 14848. 10.1074/jbc.M809542200. Green open access

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Abstract

Plasma concentrations of biologically active vitamin D (1,25(OH)(2)D) are tightly controlled via feedback regulation of renal 1 alpha-hydroxylase (CYP27B1; positive) and 24-hydroxylase (CYP24A1; catabolic) enzymes. In pregnancy, this regulation is uncoupled, and 1,25-(OH)(2)D 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 vitamin D deregulation 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
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 is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Cultured human syncytiotrophoblasts, endometrial stromal cells, type-1 diabetes-mellitus, early-pregnancy loss, d-resistant rickets, d-receptor gene, 1,25-dihydroxyvitamin d-3, 25-hydroxyvitamin d-3, dna methylation, recurrent miscarriages
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/136190
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