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Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress.

ABSTRACT: Epigenetic signatures in germ cells, capable of both responding to the parental environment and shaping offspring neurodevelopment, are uniquely positioned to mediate transgenerational outcomes. However, molecular mechanisms by which these marks may communicate experience-dependent information across generations are currently unknown. In our model of chronic paternal stress, we previously identified nine microRNAs (miRs) that were increased in the sperm of stressed sires and associated with reduced hypothalamic-pituitary-adrenal (HPA) stress axis reactivity in offspring. In the current study, we rigorously examine the hypothesis that these sperm miRs function postfertilization to alter offspring stress responsivity and, using zygote microinjection of the nine specific miRs, demonstrated a remarkable recapitulation of the offspring stress dysregulation phenotype. Further, we associated long-term reprogramming of the hypothalamic transcriptome with HPA axis dysfunction, noting a marked decreased in the expression of extracellular matrix and collagen gene sets that may reflect an underlying change in blood-brain barrier permeability. We conclude by investigating the developmental impact of sperm miRs in early zygotes with single-cell amplification technology, identifying the targeted degradation of stored maternal mRNA transcripts including sirtuin 1 and ubiquitin protein ligase E3a, two genes with established function in chromatin remodeling, and this potent regulatory function of miRs postfertilization likely initiates a cascade of molecular events that eventually alters stress reactivity. Overall, these findings demonstrate a clear mechanistic role for sperm miRs in the transgenerational transmission of paternal lifetime experiences.

SUBMITTER: Rodgers AB

PROVIDER: S-EPMC4640733 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress.

Rodgers Ali B AB Morgan Christopher P CP Leu N Adrian NA Bale Tracy L TL

Proceedings of the National Academy of Sciences of the United States of America 20151019 44

Epigenetic signatures in germ cells, capable of both responding to the parental environment and shaping offspring neurodevelopment, are uniquely positioned to mediate transgenerational outcomes. However, molecular mechanisms by which these marks may communicate experience-dependent information across generations are currently unknown. In our model of chronic paternal stress, we previously identified nine microRNAs (miRs) that were increased in the sperm of stressed sires and associated with redu ...[more]

PMID: 26483456

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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.

Dataset Information

Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress.

Publications

Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress.

Similar Datasets

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