Male mice bequeath an unexpected legacy to their progeny. Two studies published online this week in Science reveal that sperm from the rodents carry pieces of RNAs that alter the metabolism of their offspring. The RNAs spotlighted by the studies normally help synthesize proteins, so the findings point to an unconventional form of inheritance. The results are "exciting and surprising, but not impossible," says geneticist Joseph Nadeau of the Pacific Northwest Diabetes Research Institute in Seattle, Washington.
"Impossible" is exactly how biologists once described so-called epigenetic inheritance, in which something other than a DNA sequence passes a trait between generations. In recent years, however, researchers have found many examples. A male mouse's diet and stress level, for instance, can tweak offspring metabolism. Researchers are still trying to determine how offspring inherit a father's metabolic attributes and physiological condition. Some evidence implicates chemical modification of DNA. Other work by neuroscientist Tracy Bale of the University of Pennsylvania Perelman School of Medicine in Philadelphia and colleagues has found that mammalian sperm pack gene-regulating molecules called microRNAs.
The new work highlights a different class of RNAs, transfer RNAs (tRNAs). In one study, genomicist Oliver Rando of the University of Massachusetts Medical School in Worcester and colleagues delved into a case of epigenetic inheritance in which the progeny of mice fed a low-protein diet show elevated activity of genes involved in cholesterol and lipid metabolism. When Rando's group analyzed sperm from the protein-deprived males, they uncovered an increased abundance of fragments from several kinds of tRNAs. The researchers concluded the sperm acquired most of these fragments while passing through the epididymis, a duct from the testicle where the cells mature.
In the second study, a team from the Chinese Academy of Sciences in Beijing and other institutions also homed in on tRNA fragments. After feeding male mice either a high-fat or low-fat diet, the scientists injected the animals' sperm into unfertilized eggs. They then tracked the metabolic performance of the offspring, which ate a normal diet. Although progeny of the fat-eating fathers remained lean, they showed two abnormalities often found in their dads and in people who are obese or diabetic: abnormal absorption of glucose and insensitivity to insulin. To determine whether tRNA fragments were responsible for the traits, the researchers inserted the fragments into eggs fertilized with other sperm. Fragments that came from fathers that ate the high-fat diet resulted in offspring that also showed impaired glucose absorption. "We've found another link that can connect the father and offspring," says reproductive biologist Qi Chen, a study co-author, now at the University of Nevada School of Medicine in Reno.
Although tRNAs are best known for roles in protein synthesis, their fragments are turning up in other cellular situations. "Pieces of functional units that are pretty well understood can have interesting moonlighting functions," Rando says. Both studies suggest that the RNA bits alter gene activity. Rando and colleagues blocked one of the tRNA fragments inside embryonic stem cells and increased the activity of about 70 genes.
Bale says "both papers are really impressive" for digging deep into epigenetic mechanisms. And Nadeau says they should help overcome the challenge of identifying "the molecules that are responsible for inheritance outside of DNA sequences."
Researchers now need to ask "how permanent these changes are and how quickly they can be reversed by changing diet," says developmental endocrinologist Susan Ozanne of the University of Cambridge in the United Kingdom. The effects of the RNA fragments don't have to be harmful, Chen notes. "If a bad diet can influence us, I think a healthy diet can do it in the same way," he predicts.