tRNA-derived RNA processing in sperm transmits non-genetically inherited phenotypes to offspring in C. elegans

Abstract The environment encountered by an organism can modulate epigenetic information in gametes to transmit non-genetically inherited phenotypes to offspring. In mouse models, the diet of males regulates specific tRNA-derived RNAs (tDRs) in sperm. After fertilization, tDRs regulate embryonic gene expression and generate metabolic phenotypes in adult offspring through uncharacterized changes during development. Here we demonstrate that in C. elegans, tDRs also accumulate in sperm and can similarly transmit epigenetically inherited phenotypes to offspring. We identify the RNaseT2 enzyme, rnst-2, as a regulator of C. elegans tDR accumulation. RNST- 2 processes or degrades tRNA-halves, leading to short <30 nt fragments. This rnst-2 dependent regulation of tDR length distribution modulates specific tDRs in sperm which, after fertilization, regulate early embryonic and developmental gene expression, leading to adaptive phenotypes in progeny. Our findings establish tDRs as a deeply conserved carrier of intergenerational epigenetic information and position the worm as a model for dissecting paternal non-genetic inheritance mechanistically. Competing Interest Statement A.K. is co-founders of Via Scientific, Inc., a UMass Chan Medical School spin-off. A.K. is a board member of the company. A.K. and O.Y. have equity in the company. They ensure that steps have been taken to prevent these affiliations from affecting analysis integrity and are dedicated to upholding research transparency and integrity.