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Transgenerational inheritance of chronic adolescent stress: Effects of stress response and the amygdala transcriptome

ABSTRACT: Adolescent stress can impact health and well-being not only during adulthood of the exposed individual but even in future generations. To begin to unravel the molecular mechanisms underlying these long-term effects, we determined if stress administered to males during adolescence (F0) altered anxiety behaviors and gene expression profiles in the amygdala – a critical region in the control of emotional states – of their progeny in two generations (F1, F2). Male C57BL/6 mice underwent chronic unpredictable stress (CUS) for two-weeks during adolescence and were used to produce two generations of offspring. Male and female F1 and F2 animals were tested in behavioral assays to measure affective behavior and stress reactivity. Remarkably, transgenerational inheritance of paternal stress exposure produced a protective phenotype in the male, but not the female lineage. In behaviorally naïve mice (n = 5), mRNA from the amygdala was sequenced to determine the total transcriptomes and pathway analysis was employed to identify differentially expressed genes of functional interest. RNA-Seq analysis of the amygdala from F1 and F2 male offspring identified genes with altered expression in mice derived from fathers exposed to CUS. Among the differentially expressed pathway was ‘notch signaling’, which was significantly altered in F2 males. Therefore, we show that paternal stress exposure impacts future generations which manifest in behavioral changes and molecular adaptations.

ORGANISM(S): Mus musculus

PROVIDER: GSE108452 | GEO | 2018/12/19

REPOSITORIES: GEO

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Project description:Purpose: Paternal life experiences impact offspring health via germline, and epigenetic inheritance provides a potential mechanism. However, global reprogramming during offspring embryogenesis and gametogenesis represents the largest hurdle to conceptualize it. Yet, detailed characterization of how sperm epigenetic alterations carrying “environmental memory” can evade offspring embryonic reprogramming remains elusive. Methods: we profiled the sperm DNA methylation patterns of three consecutive generations (F0, F1 and F2) in both control and stress groups by using whole-genome bisulfite sequencing (WGBS). A total of 18 sperm samples were analyzed, including three biological replicates for each generation under each treatment. In addition, small RNA sequencing was carried out on paternal sperm samples to investigate whether long-term psychological stress affected the enrichment of certain sncRNAs and to identify whether they participated in mediating the occurrence and paternal inheritance of the stress-induced DMRs Rsults: Using an optimized data analysis workflow, we obtained approximately 800 million clean reads per sample (build mm10) with strand-specific coverage ~21×, and the data covered ~96.00% of the total 21,867,837 reference CpG dinucleotides. A total of 24,427, 7,975, and 5,173 differentially methylated regions (DMRs) between control and stress groups were found in the F0, F1, and F2 generations, respectively. Inter- and transgenerational inheritance of paternal DMRs were at frequencies approximately 11.36% and 0.48%, respectively. These DMRs related to genes with functional implications for psychological stress response, and tissue inheritance of these DMRs passed paternal disorders epigenetically to offspring. More importantly, these DMRs evaded offspring embryonic reprogramming through erasure and subsequent reestablishment, but not via un-erasure way. Nonetheless, their reestablishment proportions in the primitive streak (E7.5) stage were altered. Furthermore, sncRNA-seq revealed that stress-induced tsRNA, miRNA and rsRNA dysregulation in paternal sperm might play important roles in DMRs occurrence and paternal inheritance.

Project description:Background: DNA methylation (DNAme) erasure and reacquisition occurs during prenatal male germ cell development; some further remodelling takes place after birth during spermatogenesis. Environmental insults during germline epigenetic reprogramming may affect DNAme, presenting a potential mechanism for transmission of environmental exposures across multiple generations. Objectives: We investigated how germ cell DNAme is impacted by lifetime exposures to diets containing either low or high, clinically relevant, levels of the methyl donor folic acid and whether resulting DNAme alterations were inherited in germ cells of male offspring of subsequent generations. Materials and Methods: Female mice were placed on a 7-fold folic acid deficient (7FD) and 10- or 20-fold supplemented (10FS and 20FS) diets before and during pregnancy. Resulting F1 litters were weaned on the respective diets. F2 and F3 males received control diets. Genome-wide DNAme was assessed in F1 spermatogonia, and in F1, F2 and F3 sperm. Results: In F1 germ cells, a greater number of differentially methylated cytosines (DMCs) was observed in spermatogonia as compared with F1 sperm for all folic acid diets. DMCs were lower in number in F2 versus F1 sperm, while an unexpected increase was found in F3 sperm. DMCs were predominantly hypomethylated, with genes in neurodevelopmental pathways commonly affected in F1, F2 and F3 male germ cells. While no DMCs were found to be inherited inter- or transgenerationally, we observed over-representation of repetitive elements, particularly young LINEs. Discussion and Conclusion: These results suggest that the prenatal window is the time most susceptible to folate-induced alterations in sperm DNAme in male germ cells. Altered methylation of specific sites in F1 sperm was not present in later generations. However, the finding of hypomethylated young LINE1 elements in sperm from F1 to F3 males provides insight into potential mechanisms of epigenetic inheritance of the effects of folate deficiency and supplementation.

Project description:Maternal stress, anxiety, and depression increase the risk of psychiatric disorders in the progeny. These maternal effects can extend beyond the first generation and affect the grandchildren. In contrast to paternal, maternal effects can impact the offspring not only during gametogenesis, but also through fetal and early-postnatal life, increasing phenotypic complexity and the overall impact. To better understand its non-genetic structure, we dissected a complex maternally-transmitted phenotype to elementary behaviors and their corresponding transmission mechanisms. Chronic stress and depression are associated with reduced serotonin1A receptor (5-HT1AR) levels, and we reported that 5-HT1AR+/- dams transmit anxiety/stress-reactivity traits to their wild-type offspring. Here we show that the maternal effect is propagated to multiple generations, and that the behavioral traits are not transmitted in unison, but rather via parallel and segregated mechanisms, each with generation-dependent penetrance and gender specificity. The ârisk-avoidanceâ and âhypoactivityâ traits of anxiety were transmitted, via a neuro-immune pathway, consecutively from mother to the wild-type F1, F2, and occasionally F3 generation by iterative non-gametic-programming, while the âincreased stress-reactivityâ trait was transmitted to the F2 generation by gametic-programming. Iterative non-gametic-programming of anxiety was linked, via gene expression changes and clustered DNA hypo/hypermethylation at intragenic enhancers, to sphingolipid metabolism and GPCRs in the F1/F2 hippocampus, suggesting dysregulated lipid raft functioning/transmembrane signaling. Conversely, gametic-programming of behavior was predominantly associated with hypomethylation at different promoter-enhancing sequences within a set of genes with diverse neuronal functions. Since differential methylation appeared only postnatally in F2 neurons and was absent in F3 neurons, it is secondary to earlier F2 gametic changes that survive reprogramming in the early embryo, but are erased in F3 germ-cells. Our data introduce parallel and segregated non-genetic transmission of traits as a mechanism that may explain the propagation and pleiotropy of complex behavioral and psychiatric disease phenotypes across generations. Compared three generations of male offspring from wild-type and 5HT1A-R-/+ Swiss Webster mothers with two replicates per sample. Included as well is F2 embryo transfer from wild-type and het parents in wild-type surogates

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Transgenerational inheritance of chronic adolescent stress: Effects of stress response and the amygdala transcriptome

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