Two new studies in mice demonstrate how a father’s diet affects levels of specific small RNAs in his sperm, which in turn can affect gene regulation in offspring. These results add to the growing list of ways in which a male’s lifestyle can influence his offspring, including through the sperm epigenome, microbiome transfer and seminal fluid signaling.
In the first study, Qi Chen and colleagues fertilized mouse eggs using sperm from a group of male mice fed a high-fat diet (HFD), as well as a group of male mice on a normal diet (ND). The two groups of offspring exhibited no obvious differences in body weight within 16 weeks, but as early as seven-weeks-old, offspring whose fathers were in the HFD group developed impaired glucose tolerance and insulin resistance, which became more severe at 15 weeks. To assess whether the fathers’ sperm RNA contributed to these differences between the HFD and ND offspring, the researchers purified RNAs from the two groups of sperm and injected them into normal zygotes. While the HFD offspring had significantly higher blood glucose and insulin levels, their insulin sensitivity was comparable to that of ND offspring. These results suggest that RNAs from sperm of HFD males contain the information to induce glucose intolerance, but not insulin resistance. Further investigation identified tRNAs fragments, containing about 30-34 nucleotides, as the class of small RNA that caused the glucose intolerance observed in HFD offspring. A genome-wide comparison between ND and HFD offspring found significantly less expression of genes involved with ketone, carbohydrate, and monosaccharide metabolism in the HFD group.
In a second study, Upasna Sharma et al. tested whether the sperm of mice on a low protein (LP) diet experienced any changes in RNA levels. The researchers showed that small RNAs from immature sperm in the testis did not correlate with dietary effects; yet, sequencing of small RNA in mature sperm in the epididymus revealed great expression of certain RNAs. The team then isolated RNA in sperm from LP mice and controls, finding particularly high levels of a RNA, tRNA-Gly-GCC, in the LP group. Further analysis revealed that tRNA-Gly-GCC suppresses a subset of genes, including a gene that contributes to the plasticity of mouse embryonic stem cells. These results, along with those from Chen et al., demonstrate how RNA in sperm can be affected by diet, and that this can cause changes in gene regulation of offspring and associated metabolic disorder.
(A) Size distribution of sequencing reads for cauda sperm small RNAs. (B to D) 5′ tRNA fragments are shown schematically, with arrows indicating dominant 3′ ends. (E) Dietary effects on sperm small RNA content. Scatterplot shows RNA abundance (ppm) for sperm isolated from Control (x axis, log10) compared to Low Protein sperm (y axis), with various RNA classes indicated. Multiple points for tRFs result from sequence differences between genes encoding a given tRNA isoacceptor. (F) Heatmap showing RNAs responding to diet across eight paired sperm samples.