Distinctions between sex and time in patterns of DNA methylation across puberty

Abstract

Background: There are significant sex differences in human physiology and disease; the genomic sources of these differences, however, are not well understood. During puberty, a drastic neuroendocrine shift signals physical changes resulting in robust sex differences in human physiology. Here, we explore how shifting patterns of DNA methylation may inform these pathways of biological plasticity during the pubertal transition. In this study we analyzed DNA methylation (DNAm) in saliva at two time points across the pubertal transition within the same individuals. Our purpose was to compare two domains of DNAm patterns that may inform processes of sexual differentiation 1) sex related sites, which demonstrated differences between males from females and 2) time related sites in which DNAm shifted significantly between timepoints. We further explored the correlated network structure sex and time related DNAm networks and linked these patterns to pubertal stage, assays of salivary testosterone, a reliable diagnostic of free, unbound hormone that is available to act on target tissues, and overlap with androgen response elements.Results: Sites that differed by biological sex were largely independent of sites that underwent change across puberty. Time-related DNAm sites, but not sex-related sites, formed correlated networks that were associated with pubertal stage. Both time and sex DNAm networks reflected salivary testosterone levels that were enriched for androgen response elements, with sex-related DNAm networks being informative of testosterone levels above and beyond biological sex later in the pubertal transition. Conclusions: These results inform our understanding of the distinction between sex- and time-related differences in DNAm during the critical period of puberty and highlight a novel linkage between correlated patterns of sex-related DNAm and levels of salivary testosterone.

Analysis of transcriptional changes in the immune system associated with pubertal development in a longitudinal cohort of children with asthma

“…Furthermore, regions experiencing changes in methylation status in both sexes show changes with higher magnitude in females 24 . In contrast, other studies on pre-and post-pubertal subjects found limited differences in DNA methylation patterns between sexes 23,25 . These inconsistencies may be due to age differences between studies and could be further investigated by employing a study design that focuses on all pubertal developmental stages rather than comparing pre-and post-pubertal stages only.…”

“…Previous studies of DNA methylation changes between pre-and post-puberty in females found overrepresentation of genes involved in immune and inflammatory responses 24,25,27 , reproductive hormone signaling 24 , and other physiological changes related to growth and development 26 . Our results allowed a more fine-grained insight into the changes in the immune system that accompany sexual maturation of females.…”

“…Previous genomic studies have focused on exploring DNA methylation changes between pre-and postpuberty [24][25][26][27][28] in peripheral blood immune cells. Yet, despite the clear evidence of epigenetic reprogramming during pubertal development, gene expression changes throughout puberty remain understudied.…”

“…The molecular mechanisms underlying the physiological and pathological changes in the immune system during puberty remain understudied and largely uncharacterized. Previous studies have explored the effects of puberty on DNA methylation [21][22][23][24][25][26] in peripheral blood immune cells. DNA methylation is an important epigenetic mark regulating gene expression during development and aging 27 .…”

Sex-specific DNA methylation in saliva from the multi-ethnic Fragile Families and Child Wellbeing Study

“…Sex differences in DNAm are expected on the X chromosome in humans due to X chromosome inactivation (Hall et al, 2014;Duncan et al, 2018). However, sex differences in DNAm have also been reported on autosomal chromosomes in numerous tissues including blood (7,(11)(12)(13), buccal cells (14,15), the prefrontal cortex (16), and the placenta (17,18). The number of differentially methylated sites ranged from a few hundred to nearly ten thousand in these studies, depending on the tissue, DNAm array, and available sample sizes.…”