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Single paternal dexamethasone challenge programs offspring metabolism and reveals multiple candidates in RNA-mediated inheritance.

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Gapp, Katharina 
Parada, Guillermo E 
Gross, Fridolin 
Corcoba, Alberto 
Kaur, Jasmine 


Single traumatic events that elicit an exaggerated stress response can lead to the development of neuropsychiatric conditions. Rodent studies suggested germline RNA as a mediator of effects of chronic environmental exposures to the progeny. The effects of an acute paternal stress exposure on the germline and their potential consequences on offspring remain to be seen. We find that acute administration of an agonist for the stress-sensitive Glucocorticoid receptor, using the common corticosteroid dexamethasone, affects the RNA payload of mature sperm as soon as 3 hr after exposure. It further impacts early embryonic transcriptional trajectories, as determined by single-embryo sequencing, and metabolism in the offspring. We show persistent regulation of tRNA fragments in sperm and descendant 2-cell embryos, suggesting transmission from sperm to embryo. Lastly, we unravel environmentally induced alterations in sperm circRNAs and their targets in the early embryo, highlighting this class as an additional candidate in RNA-mediated inheritance of disease risk.



Developmental biology, Embryology, Molecular physiology, Transcriptomics

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Elsevier BV


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Wellcome Trust (219475/Z/19/Z)
Wellcome Trust (203144/Z/16/Z)
Cancer Research UK (A27826)
Cancer Research UK (C6946/A24843)
Cancer Research Uk (None)
Cancer Research UK (18583)
KG was funded by the Swiss National Science Foundation early postdoc and advanced postdoc mobility a SPARK and Novartis foundation grant. Some of this work was supported by Cancer Research UK (C13474/A18583, C6946/A14492) and Wellcome (104640/Z/14/Z, 092096/Z/10/Z) to EAM. GP and MH were supported by a core grant from the Wellcome Trust. The lab of JB is currently funded by the ETH Zurich, SNSF Project Grant 310030_172889/1, ETH Research Grant ETH-20 19-1, the Kurt und Senta Herrmann-Stiftung, the Botnar Research Center for Child Health and a 3R Competence Center Project Grant. JK was supported by a Swiss-european mobility programme scholarship.