Childhood Bone Mineral Content Is Associated With Methylation Status of the RXRA Promoter at Birth

Abstract

Maternal vitamin D deficiency has been associated with reduced offspring bone mineral accrual. Retinoid-X receptor-alpha (RXRA) is an essential cofactor in the action of 1,25-dihydroxyvitamin D (1,25[OH] 2 -vitamin D), and RXRA methylation in umbilical cord DNA has been associated with later offspring adiposity. We tested the hypothesis that RXRA methylation in umbilical cord DNA collected at birth is associated with offspring skeletal development, assessed by dual-energy X-ray absorptiometry, in a population-based motheroffspring cohort (Southampton Women's Survey). Relationships between maternal plasma 25-hydroxyvitamin D (25[OH]-vitamin D) concentrations and cord RXRA methylation were also investigated. In 230 children aged 4 years, a higher percent methylation at four of six RXRA CpG sites measured was correlated with lower offspring bone mineral content (BMC) corrected for body size (b ¼ À2.1 to À3.4 g/SD, p ¼ 0.002 to 0.047). In a second independent cohort (n ¼ 64), similar negative associations at two of these CpG sites, but positive associations at the two remaining sites, were observed; however, none of the relationships in this replication cohort achieved statistical significance. The maternal free 25(OH)-vitamin D index was negatively associated with methylation at one of these RXRA CpG sites (b ¼ À3.3 SD/unit, p ¼ 0.03). Thus, perinatal epigenetic marking at the RXRA promoter region in umbilical cord was inversely associated with offspring size-corrected BMC in childhood. The potential mechanistic and functional significance of this finding remains a subject for further investigation.

Genome-wide detection of CNVs in Chinese indigenous sheep with different types of tails using ovine high-density 600K SNP arrays

“…Unsaturated fatty acids bind to PPARA , which is highly expressed in the liver, skeletal muscle, heart, and kidney38, where it activates genes that are involved in fatty acid metabolism. RXRA is a member of the nuclear hormone superfamily and forms heterodimers with a number of nuclear receptors, including the thyroid hormone receptor, vitamin D receptor, GR , and PPAR 39. RXRA can mediate heterodimerization with retinoic acid receptors ( RARs ) and is essential for the functional activation of RARs by their ligands40.…”

“…RXRA can mediate heterodimerization with retinoic acid receptors ( RARs ) and is essential for the functional activation of RARs by their ligands40. RXRA plays a role in lipid homeostasis4142 and foetal development39. KLF11 (Kruppel-like factor 11) is a member of the Kruppel-like factor family and is expressed in many human tissues43.…”

Maternal Dietary Vitamin D Does Not Program Systemic Inflammation and Bone Health in Adult Female Mice Fed an Obesogenic Diet

“…Observational studies demonstrate that maternal vitamin D status may be a predictor of offspring bone mineral accrual in females at 9 years of age [11] and up to 20 years of age in both males and females [12]. This may be explained via epigenetic mechanisms including higher methylation of the retinoid-X receptor-alpha (RXRA) cofactor, required for 1,25-dihydroxyvitamin D activation, in offspring born to mothers deficient in vitamin D [13]. This is an example of a concept of early nutrition that invariably impacts later health outcomes and is referred to as nutritional programming.…”

Vitamin D, muscle and bone: Integrating effects in development, aging and injury

“…Maternal vitamin D status is indirectly associated with fetal bone mineral content via methylation at 4 sites of the RXRA in umbilical cord tissue (Harvey et al, 2014;Jaenisch and Bird, 2003). This indicates a novel epigenetic role for vitamin D in embryonic skeletal development.…”