Abstract
BackgroundThe 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.ObjectiveTo identify global DNA methylation changes that arise across the window of puberty in girls and boys.MethodsGenome-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.ResultsOur 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 × 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.ConclusionEpigenetic 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.
Highlights
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
Our results show striking differences between boys and girls and suggest that epigenetic changes occurring between the ages of 8 and 14 in girls may contribute to estrogen, endocrine, and immune signaling pathways, and play a role in sex-specific differences in susceptibility to immune-mediated and endocrine diseases later in life
Almstrup et al used peripheral blood leukocytes (PBLs) while we used peripheral blood mononuclear cells (PBMCs), and Almstrup et al combined both sexes for analysis and used sex as a covariate to identify 457 Differentially methylated probe (DMP) in the combined sample, whereas we focused our studies on methylation changes that were unique to boys or to girls and identified sex-specific puberty DMPs (Fig. 1)
Summary
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. Many anatomical and physiological differences between boys and girls emerge around the time of puberty, a period marked by considerable metabolic and hormonal change as well as dynamic physiologic transitions This period is characterized by shifts in male and female sex steroid hormone production [1], as well as sex disparities in the onset and remission of asthma [2, 3] and the development of autoimmune diseases and cardiometabolic risk factors, such as lipid profiles [4, 5], blood pressure [6, 7], and insulin resistance [8], among others. Because boys and girls were analyzed together in this study, little is still known about epigenetic changes that arise during the window of puberty in males and females, which would differ if these changes are linked to the extreme dimorphism that arises during this period
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