Abstract
Pathophysiological mechanisms for depression/anxiety are largely unknown. Evidence for transgenerational transmission of acquired epigenetic marks remains limited. We bred unstressed (US) female mice with adolescently restraint-stressed (RS), social instability-stressed (SI) or US males to produce RS, SI and control F1 offspring, respectively. Compared to controls, while paternal RS decreased anxiety-like behavior (ALB) in both female and male offspring, paternal SI increased ALB only in female offspring. Next-generation sequencing and bioinformatics using RS and SI female offspring identified 5 candidate anxiety-transmitting (CAT) genes; each showed a consistent pattern of DNA methylation from F0 spermatozoa through F1 blastocysts to fetal and adult hippocampi. Further analyses validated 4 CAT genes, demonstrated that paternal SI caused ALB differences between male and female offspring through modifying the CAT genes, and indicated a strong correlation between inflammation and ALB pathogenesis and an important function for intronic DNA methylation in regulating ALB-related genes. In conclusion, this study identified important CAT genes and suggested the possibility that stresses on males might alter offspring’s ALB by modifying sperm DNA methylation.
Highlights
Pathophysiological mechanisms for depression/anxiety are largely unknown
Among the 3 models tested in this study, the RS/social instability (SI) model was found more suitable to produce significant differences than the RS and control (RS/C) or SI and control (SI/C) models for study of anxiety-like behavior (ALB) pathogenesis and for identification of candidate anxiety-transmitting (CAT) genes
Our next-generation sequencing and bioinformatics using the RS and SI female offspring identified 5 candidate CAT genes; each showed a consistent pattern of DNA methylation from F0 spermatozoa through F1 blastocysts to fetal and adult hippocampi
Summary
Pathophysiological mechanisms for depression/anxiety are largely unknown. Evidence for transgenerational transmission of acquired epigenetic marks remains limited. Among studies that observed epigenetic alterations in spermatozoa, only a few analyzed noncoding RNA p rofiling[8,14] or single gene DNA methylation[15] following stress treatment of the sires; next-generation sequencing and systematic studies on the routes by which epigenetic signals are delivered from gametes through embryos to adult organs are lacking. Both mouse models of restraint stress (RS) and social instability (SI) have been used to study the mechanisms by which stressors applied at different life stages cause mental alterations in the current or subsequent generations[16]. A direct comparison by next-generation sequencing between female offspring sired by adolescently RS- and SI-stressed mice would definitely reveal more in-depth knowledge on epigenetic transmission of anxiety
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