父本低蛋白饮食的代际效应需要ATF7依赖的表观遗传变化。

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

作者信息

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

机构信息

RIKEN Cluster for Pioneering Research, Tsukuba, Ibaraki 305-0074, Japan.

出版信息

Mol Cell. 2020 May 7;78(3):445-458.e6. doi: 10.1016/j.molcel.2020.02.028. Epub 2020 Mar 19.

DOI:10.1016/j.molcel.2020.02.028

PMID:32197065

Abstract

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.

摘要

父方的饮食状况可能会导致子代出现代谢紊乱。我们分析了应激依赖性表观遗传调节因子环磷酸腺苷依赖性转录因子7（ATF7）在父方低蛋白饮食（pLPD）诱导的小鼠肝脏基因表达变化中的作用。Atf7突变导致的子代表型与pLPD导致的相似，而当使用父方为Atf7基因敲除的小鼠时，pLPD的影响几乎消失。ATF7可与约2300个基因的启动子区域结合，包括睾丸生殖细胞（TGCs）中与胆固醇生物合成相关的基因和tRNA基因。低蛋白饮食通过活性氧（ROS）诱导TGCs中的p38使ATF7磷酸化。这导致ATF7释放，并使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，并诱导精子中一些tRNA片段的表达。这些结果表明，TGCs中低蛋白饮食诱导的且依赖于ATF7的表观遗传变化在父方饮食诱导的子代代谢重编程中起重要作用。