Sperm RNA code programmes the metabolic health of offspring

Abstract

Mammalian sperm RNA is increasingly recognized as an additional source of paternal hereditary information beyond DNA. Environmental inputs, including an unhealthy diet, mental stresses and toxin exposure, can reshape the sperm RNA signature and induce offspring phenotypes that relate to paternal environmental stressors. Our understanding of the categories of sperm RNAs (such as tRNA-derived small RNAs, microRNAs, ribosomal RNA-derived small RNAs and long non-coding RNAs) and associated RNA modifications is expanding and has begun to reveal the functional diversity and information capacity of these molecules. However, the coding mechanism endowed by sperm RNA structures and by RNA interactions with DNA and other epigenetic factors remains unknown. How sperm RNA-encoded information is decoded in early embryos to control offspring phenotypes also remains unclear. Complete deciphering of the 'sperm RNA code' with regard to metabolic control could move the field towards translational applications and precision medicine, and this may lead to prevention of intergenerational transmission of obesity and type 2 diabetes mellitus susceptibility.

Fig. 1 |. Information capacity and functional specificity of the sperm RNA code.

Schematic representation of the sperm RNA code (an interconnected combination of RNA expression and RNA modification profile) that reflects paternal environmental exposure and mediates the transmission of specific phenotypes to the offspring. Different paternal information can be encoded in specific subsets of sperm RNA fractions. lncRNA, long non-coding RNA; miRNA, microRNA; piRNA, Piwi-interacting RNA; rsRNA, ribosomal RNA-derived small RNA; tsRNA, tRNA-derived small RNA.

Fig. 2 |. Potential mechanisms in transformation of the sperm RNA code during embryo development.

a | In mouse early embryo, the tRNA-derived small RNA (tsRNA) expression level increases from the four-cell to eight-cell transition, and the tsRNA composition is similar to that of mature sperm. At certain genomic loci, the H3K4me3 pattern in sperm is initially removed in zygotes but re-established in both paternal and maternal chromosomes from the late two-cell embryo stage^,. It would be interesting to explore the causal relationship between tsRNAs and the H3K4me3 pattern in sperm and embryo. b | The hypothesis of tsRNA-mediated ribosome heterogeneity that generates biased translational specificity towards different pools of mRNA subpopulations. c | A hypothetical scenario to explain how the initial abnormal metabolic transcriptome induced by sperm RNA can be maintained throughout embryo development. This could be triggered by a self-amplifying loop of abnormal metabolic transcriptome, metabolites and epigenome during embryo development. Acyl-CoA, acetyl coenzyme A; HFD, high-fat diet; SAM, S-adenosyl methionine.

Fig. 3 |. Future applications and precision medicine based on high resolution of sperm RNA code.

a | Future application of third-generation RNA-sequencing platform to simultaneously obtain full RNA sequences and meanwhile pinpoint different RNA modifications at base resolution. b | Future use of sperm RNA code information as clinical guidance for well-timed pregnancy and to reduce the susceptibility to metabolic disorder in the offspring.