Abstract
BackgroundThere 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.ResultsSites 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.ConclusionsThese 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.
Highlights
There are significant sex differences in human physiology and disease; the genomic sources of these differences, are not well understood
We explored the independence of time- and sex-related DNA methylation (DNAm) sites, the correlated networks of time- and sex-related DNAm sites and the specific patterns that drove these networks, and their associations with pubertal maturation, as assessed by pubertal stage, salivary testosterone, and overlap with androgen response elements
We found that sex-related sites were largely independent of time-shifting sites and, further, formed correlated networks of DNAm patterns that synchronized with salivary testosterone levels later in the pubertal transition
Summary
There are significant sex differences in human physiology and disease; the genomic sources of these differences, are not well understood. Puberty is characterized by a drastic neuroendocrine shift signaling physical changes, such as the development of secondary sex characteristics and the redistribution of adipose tissue, and organizational/activational effects of adrenal and gonadal hormones on brain development [1, 2]. With these changes, there are robust sex differences in human physiology and in the prevalence and symptomatology of a number of mental and physical health disorders [3]. Pubertal levels of gonadal hormones have been studied extensively in relation to physical and neural development in adolescents [17], the functional genetic pathways that are regulated to produce these changes are just beginning to be explored in humans [18,19,20,21,22]
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