Placenta-specific Methylation of the Vitamin D 24-Hydroxylase Gene

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) 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.In eutherian mammals, proper fetal growth and development are dependent on the formation and function of the placenta. In combination with the maternal decidua, cells of the placenta (primarily trophoblasts) regulate the exchange of nutrients, growth factors, oxygen, and waste between maternal and fetal circulations. The placenta also protects the developing pregnancy from the maternal immune system (1).Although mammalian placentas share a basic common function in modulating exchange at the fetomaternal interface, it is clear that the human placenta is unique in structure and function (2). Animal models may therefore be of limited value in fully dissecting processes underlying certain aspects of human pathologies, such as pre-eclampsia and gestational trophoblastic disease (3). An examination of human placentation is therefore critical in understanding its unique function and potential role in disease.The biologically active form of vitamin D (1,25-(OH) 2 D) 4 is a potent secosteroid hormone. Its wide ranging actions include regulating calcium and phosphorus homeostasis, immune system modulation, cellular differentiation, and apoptosis (4 -6). It also has potent antiproliferative effects (7-9). Vitamin D deficiency has been linked to several adverse pregnancy outco...

Characterization of an animal model of pregnancy-induced vitamin D deficiency due to metabolic gene dysregulation

“…In normal human placenta and decidua from the first and second trimesters, expression of CYP27b1 and VDR is increased by more than 10-fold compared with endometrium, whereas the contrary is true for placental CYP24a1 expression (10). A recent study has demonstrated that CYP24a1 expression in the human placenta is downregulated by hypermethylation of its promoter (37). Increased maternal 1␣,25-(OH) 2 -D levels during pregnancy are not a consequence of increased PTH, which remains low during human and rodent pregnancy (24,38).…”

“…calcitriol; CYP24a1; metabolism; kidney; placenta THE SECOSTEROID VITAMIN D has well-established classic effects on bone metabolism and mineral homeostasis (7,37). Vitamin D 3 (cholecalciferol) is generated from 7-dehydrocholesterol by a photolytic (UVB) conversion in the skin epidermis and from dietary animal sources, and vitamin D 2 (ergocalciferol) is obtained by dietary plant sources.…”

Vitamin D and Spectrum of Its Roles

“…No methylation was detected in any somatic human tissue tested. Methylation was also evident in marmoset and mouse placental tissue [9]. Epigenetics also plays important role.…”

The effect of vitamin D on women’s reproductive health

“…Доказано, что плацента способна синтези-ровать 1,25(oH) 2 D. Существуют данные, кото-рые показывают, что производство плацентой 1,25(oH) 2 D в течение беременности на фоне увеличенного синтеза этого же витамина поч-ками превышает скорость выведения его из орга низма, способствуя его накоплению [58]. как следствие, у женщин в третьем триместре беременности содержание 1,25(oH) 2 D в сыво-ротке крови в два раза выше, чем у неберемен-ных или у женщин после родов [59,60].…”