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.

中文翻译：

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父系低蛋白饮食的代际效应需要ATF7依赖的表观遗传变化。

父亲的饮食条件可能会导致后代的代谢异常。我们已经分析了应激依赖性表观遗传调控子环AMP依赖性转录因子7（ATF7）在小鼠肝脏中父本低蛋白饮食（pLPD）诱导的基因表达变化中的作用。Atf7 +/-突变引起的后代表型与pLPD引起的表型相似，当使用父本Atf7 +/-小鼠时，pLPD的作用几乎消失。ATF7与约2,300个基因的启动子区域结合，包括睾丸生殖细胞（TGC）中与胆固醇生物合成相关的基因和tRNA基因。LPD通过TGC中的活性氧（ROS）通过p38诱导ATF7磷酸化。这导致ATF7的释放和其靶基因上的组蛋白H3K9二甲基化（H3K9me2）减少。这些表观遗传变化得以维持，并诱导精子中某些tRNA片段的表达。这些结果表明，TGDs中LPD诱导的和ATF7依赖的表观遗传学变化在父本饮食引起的后代代谢重编程中起重要作用。