Sometimes a novel, a poem, or a song can enjoy such an outpouring from adoring fans that its influence can echo across the ages; however, recent work led by the lab of Daria Peleg-Raibstein (ETH Zurich, Switzerland) has established that mom’s unhealthy lifestyle can also echo across the ages leading to an observed negative impact in offspring.
Previous research by the talented team discovered a transgenerational effect: mouse mothers fed on a high-fat diet (HFD) while pregnant produced pups that that gorged on palatable foods and displayed higher sensitivity to drugs and alcohol. Interestingly, this hedonistic and obesogenic phenotype transmitted through to the third generation (F3) without further exposure of offspring to an HFD. Furthermore, this process occurred alongside a sustained reduction in dopamine levels, but without significant changes to CpG methylation in first- and second-generation sperm, thereby almost certainly ruling out DNA methylation as the primary controlling mechanism.
So how were these effects passed down through the generations? To investigate how mothers transmitted these pleasure-seeking characteristics to their offspring, the authors examined the role of sperm small non-coding RNAs (sncRNAs) in producing an intergenerational effect, given their potential as mediators of acquired traits following postnatal trauma or paternal diet. So, Sarker and colleagues lifted the needle off their scratchy vinyl copy of “Subterranean Homesick Blues”, put aside their well-worn copy of “To Kill a Mockingbird”, and demonstrated that sperm tRNA-derived small RNAs have an intergenerational effect that may allow mom’s hedonistic lifestyle to echo through the ages:
- Injection of total sperm RNA from first-generation male offspring (F1) of mothers fed on a long-term HFD (F0) into healthy fertilized oocytes transmits obesogenic and hedonistic traits to the next generation (F2)
- Deep-sequencing analysis of sperm small non-coding (nc)RNAs revealed that mothers exposed to an HFD give birth to male offspring expressing a larger proportion of sperm transfer RNA-derived small RNAs (tsRNAs), which are predominantly comprised of 5′ tRNA halves
- Injection of isolated sperm tsRNAs into healthy
fertilized oocytes promotes the appearance of obesogenic and hedonistic traits
- Predicted targets transcripts of differentially expressed sperm tsRNAs include factors involved in addiction pathology, which also display alterations in expression in the brain’s reward regions of first-generation males and resultant offspring
- Seven candidate genes – CHRNA2, GRIN3A, VAV3, ZCCHC11, EEFA1, DHRS3, and DAB2IP – play functional roles in neuronal growth, differentiation, axonal guidance, dendritic spine formation, and maturation in the developing brain
- However, the subtle changes observed with sperm tsRNAs alone (compared to total sperm RNA) suggest a complex interaction with other sperm ncRNAs and also DNA methylation, histone modifications, and chromatin remodeling, in the transmission of the whole phenotype
Overall, the data produced by the group demonstrates a role for sperm tsRNAs in the intergenerational transmission of maternal HFD-induced addictive-like behaviors and obesogenic phenotypes. The team hopes to continue chasing these echoes through the ages and now plans to delineate the roles for RNA modification machinery and/or the interplay between sperm tsRNA and other epigenetic marks in alterations to sperm tsRNA profiles and the maintenance of epigenetic memory in later generations.
Is this paper the next “classic” whose results will echo through the ages? To find out, see PNAS, May 2019.