51 Intergenerational transmission of paternal environmental effects via sperm small RNAs in mice

Abstract Abstract: Introduction Transmission of parental traits to offspring is the most fundamental process for the perpetuation of life and is vital for the process of evolution. Although there is mounting evidence from worms to humans that parental environment can influence phenotypes in offspring, the mechanism of such intergenerational inheritance remains deeply mysterious. Our previous studies implicated sperm small RNAs in intergenerational epigenetic inheritance of paternal environmental effects. We found that cleavage products of tRNAs, known as tRNA-derived small RNAs or tRNA fragments (tRF), are highly abundant in mature sperm and environmental conditions alter their levels. A 5’ fragment of tRNA-Valine-CAC-2 (tRFValCAC) as one of the most abundant tRNA fragments in mature mouse sperm. tRFValCAC is enriched in sperm during epididymal maturation, and extracellular vesicles (EVs) secreted by epididymal epithelial cells can deliver tRFValCAC to sperm. Objective Here, we investigated how tRFValCAC is delivered to sperm and what functions it carries out upon deposition in the embryo at fertilization to elucidate the mechanism of sperm tRF-mediated intergenerational inheritance. Methods We used a combination of RNA-sequencing, assisted reproduction, and embryo microinjections to study the dynamics and functions of tRFValCAC. Results Our studies demonstrate that heterogeneous nuclear ribonucleoprotein A/B (hnRNPAB) binds tRFValCAC in the epididymis and regulates its abundance in EVs, thereby modulating its levels in sperm. Inhibition of tRFValCAC in preimplantation embryos alters transcript abundance of genes involved in RNA splicing and mRNA processing, dysregulates alternative splicing, and delays preimplantation development. Conclusions Our work revealed that a sperm-enriched tRF regulates early embryonic gene expression and the pace of preimplantation development, providing a potential mechanism of sperm small RNAs-mediated intergenerational inheritance. (Supported by NIH 1DP2AG066622-01, Searle Scholars Program 20-SSP-109)