Environmental factors affecting parents play a role in programming the health of their offspring. For example, when parents eat low-protein or high-fat diets, it can lead to metabolic disorders in their adult offspring. In a study published today in Molecular Cell, RIKEN researchers identified the molecular events underlying this phenomenon in mice.
This phenomenon is due to epigenetics: heritable changes in gene activity that don’t change the underlying DNA sequence. However, until now, the details were unknown. In the new study, RKEN researchers discovered that a protein called ATF7 is essential for the intergenerational effect. ATF7 is a transcription factor, meaning that it regulates when genes are turned on and off.
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The researchers fed male and female mice on normal or low-protein diets and then allowed them to mate. Once the offspring were adults, the researchers found that gene expression differed for hundreds of genes in the liver—many of which are involved in cholesterol metabolism—depending on which diet the father was on. However, when they used genetically engineered male mice that lacked one copy of the ATF7 gene, gene expression in the offspring did not differ depending on the father’s diet.
Based on these findings, the team searched for and found genes in sperm cells that are controlled by ATF7, including those for fat metabolism in the liver and cholesterol production. Experiments revealed that when fathers-to-be ate low-protein diets, ATF7 came loose and no longer bound to these genes. This, in turn, reduced a particular modification to histone proteins, with a net effect that these sperm-cell genes were turned on, rather than the normal situation of being turned off.
“We hope that people, especially those who have poor nutrition by choice, will pay more attention to their diet when planning for the next generation,” Ishii says “Our results indicate that diets with more protein and less fat are healthier not just for everyone’s own body, but also for sperm and the health of potential children.”