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Wednesday, October 28, 2015

Transgenerational Epigenetic Programming Via Sperm MicroRNA Recapitulates Effects of Paternal Stress

Proceedings of the National Academy of Sciences

By Ali B. RodgersChristopher P. MorganN. Adrian Leu and Tracy L. Bale
Edited by Bruce S. McEwen, The Rockefeller University, New York, NY

September 11, 2015

"Overall, these findings demonstrate a clear mechanistic role for sperm miRs in the transgenerational transmission of paternal lifetime experiences."

Significance: Studies examining paternal exposure to diverse environmental stimuli propose that epigenetic marks in germ cells, including small noncoding RNAs such as microRNA (miR), transmit experience-dependent information from parent to offspring. However, these nongenetic mechanisms of transgenerational inheritance are poorly understood, specifically how these germ-cell marks may act postfertilization to enact long-term changes in offspring behavior or physiology.

In this study, through zygote microinjection of nine specific sperm miRs previously identified in our paternal stress mouse model, we demonstrate that sperm miRs function to reduce maternal mRNA stores in early zygotes, ultimately reprogramming gene expression in the offspring hypothalamus and recapitulating the offspring stress dysregulation phenotype.

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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.

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