Global DNA methylation changes spanning puberty are near predicted estrogen-responsive genes and enriched for genes involved in endocrine and immune processes

Abstract

Background: The changes that occur during puberty have been implicated in susceptibility to a wide range of diseases later in life, many of which are characterized by sex-specific differences in prevalence. Both genetic and environmental factors have been associated with the onset or delay of puberty, and recent evidence has suggested a role for epigenetic changes in the initiation of puberty as well. Objective: To identify global DNA methylation changes that arise across the window of puberty in girls and boys. Methods: Genome-wide DNA methylation levels were measured using the Infinium 450K array. We focused our studies on peripheral blood mononuclear cells (PBMCs) from 30 girls and 25 boys pre- and post-puberty (8 and 14 years, respectively), in whom puberty status was confirmed by Tanner staging. Results: Our study revealed 347 differentially methylated probes (DMPs) in females and 50 DMPs in males between the ages of 8 and 14 years (FDR 5%). The female DMPs were in or near 312 unique genes, which were over-represented for having high affinity estrogen response elements (permutation P < 2.0 x 10(-6)), suggesting that some of the effects of estrogen signaling in puberty are modified through epigenetic mechanisms. Ingenuity Pathway Analysis (IPA) of the 312 genes near female puberty DMPs revealed significant networks enriched for immune and inflammatory responses as well as reproductive hormone signaling. Finally, analysis of gene expression in the female PBMCs collected at 14 years revealed modules of correlated transcripts that were enriched for immune and reproductive system functions, and include genes that are responsive to estrogen and androgen receptor signaling. The male DMPs were in or near 48 unique genes, which were enriched for adrenaline and noradrenaline biosynthesis (Enrichr P = 0.021), with no significant networks identified. Additionally, no modules were identified using post-puberty gene expression levels in males. Conclusion: Epigenetic changes spanning the window of puberty in females may be responsive to or modify hormonal changes that occur during this time and potentially contribute to sex-specific differences in immune-mediated and endocrine diseases later in life.