ATF7-Dependent Epigenetic Changes Are Required for the Intergenerational Effect of a Paternal Low-Protein Diet

• Published in: Molecular cell 2020-05, Vol.78 (3), p.445-458.e6
• Main Authors: Yoshida, Keisuke, Maekawa, Toshio, Ly, Nhung Hong, Fujita, Shin-ichiro, Muratani, Masafumi, Ando, Minami, Katou, Yuki, Araki, Hiromitsu, Miura, Fumihito, Shirahige, Katsuhiko, Okada, Mariko, Ito, Takashi, Chatton, Bruno, Ishii, Shunsuke
• Format: Article
• Language: English
• Subjects: ATF7; Biotechnology; cholesterol biosynthesis; epigenetic regulation; histone modification; intergenerational inheritance; Life Sciences; paternal diet; ROS
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.02.028

Paternal dietary conditions may contribute to metabolic disorders in offspring. We have analyzed the role of the stress-dependent epigenetic regulator cyclic AMP-dependent transcription factor 7 (ATF7) in paternal low-protein diet (pLPD)-induced gene expression changes in mouse liver. Atf7+/– mutations cause an offspring phenotype similar to that caused by pLPD, and the effect of pLPD almost vanished when paternal Atf7+/– mice were used. ATF7 binds to the promoter regions of ∼2,300 genes, including cholesterol biosynthesis-related and tRNA genes in testicular germ cells (TGCs). LPD induces ATF7 phosphorylation by p38 via reactive oxygen species (ROS) in TGCs. This leads to the release of ATF7 and a decrease in histone H3K9 dimethylation (H3K9me2) on its target genes. These epigenetic changes are maintained and induce expression of some tRNA fragments in spermatozoa. These results indicate that LPD-induced and ATF7-dependent epigenetic changes in TGCs play an important role in paternal diet-induced metabolic reprograming in offspring. [Display omitted] •ATF7 is required for paternal diet-induced expression changes in mouse offspring•ATF7 binds to the promoter regions and induces H3K9me2 in testicular germ cells•Low protein diet causes ATF7 activation and H3K9me2 reduction via ROS production•ATF7 regulates epigenetic status and small RNA expression profile in spermatozoa Yoshida et al. report that ATF7 is a key mediator of paternal low-protein diet (LPD)-induced intergenerational inheritance. In the testis, LPD induces ATF7 activation via ROS, leading to H3K9me2 reduction on ATF7 target genes. This epigenetic change is maintained in spermatozoa and affects the pattern of small RNA expression.