Although we’ve known for a while that paternal stress can lead to problems down the road for their offspring thanks to DNA methylation and histone modifications, non-coding RNAs have now come full circRNA.
In their latest, a talented team from the lab of Eric Miska (University of Cambridge, UK) decided to find out which RNA molecules are transmitted following a stressful paternal event. Dexamethasone (Dex) is a good drug proxy for stress, acting as an agonist for glucocorticoid receptors. The drug has been in the news more recently, as an effective treatment for COVID-19 induced respiratory infections. In a mouse model, a single paternal Dex injection results in:
- Offspring with higher body mass indices (BMIs)
- Females with impaired glucose tolerance
- Males with decreased glucose levels in response to a glucose injection
These phenotypic differences follow transcriptomic changes in sperm:
- Transfer RNA-derived small fragments (tsRNAs), microRNAs (miRNAs), and ribosomal RNAs (rRNAs) are all differentially expressed 14 days after Dex injection (assessed via ultradeep small RNA sequencing)
- One small RNA, tsArg-CCT-2, is potentially taken up by naïve sperm from exosomes in the caput epididymis
- tsArg-CCT-2 expression increases as sperm mature and migrate from caput to cauda, and its expression is greatly upregulated in response to Dex in cauda sperm (mature)
- Two circular RNAs (circRNAs) are also upregulated in the mature cauda sperm in response to Dex
- Several tsRNAs affected in sperm are also downregulated in two-cell embryos fertilized by sperm from Dex-treated males
- Embryonic gene expression also shifts – several genes involved in early development are also differentially expressed, including targets of the upregulated circRNAs (Bcap31, Hprt, Rbbp7, and Tcl1), initially detected using 2-cell single-embryo sequencing
Together, the researchers show that a single stressful paternal event (Dex injection) is sufficient to result in phenotypic changes in the offspring. These changes are likely the result of changes in sperm RNA payload, including small RNAs and circRNAs that alter embryonic gene expression.
First author, Katharina Gapp adds, “Since such a brief treatment induces changes in yet another class of noncoding RNA one wonders what other one-off experiences induce changes in CircRNA and how they interact with other germline factors to contribute to disease risk in the progeny.”
Circle around and see the full details in iScience, August 2021.