Wei Suhua, Luo Shiwei, Zhang Haifeng, Li Yandong, Zhao Juan
Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou, China.
Genes Nutr. 2023 Aug 19;18(1):12. doi: 10.1186/s12263-023-00731-4.
Paternal high-fat diet (HFD) can alter the epigenetics of sperm DNA, resulting in the transmission of obesity-related traits to the offspring. Previous studies have mainly focused on the HFD-induced changes in DNA methylation of imprinted genes, overlooking the potential involvement of non-imprinted genes in this process. SETD2, an important epigenetically-regulated gene known for its response to environmental stress, remains poorly understood in the context of high-fat diet-induced epigenetic changes. Here we examined the effect of obesity from a HFD on paternal SETD2 expression and methylation in sperm, and embryos at the blastocyst stage and during subsequent development, to determine the alteration of SETD2 in paternal intergenerational and transgenerational inheritance. The result showed that mice fed with HFD for two months had significantly increased SETD2 expression in testis and sperm. The paternal HFD significantly altered the DNA methylation level with 20 of the 26 CpG sites being changed in sperm from F0 mice. Paternal high-fat diet increased apoptotic index and decreased total cell number of blastocysts, which were closely correlated with DNA methylation level of sperm. Out of the 26 CpG sites, we also found three CpG sites that were significantly changed in the sperm from F1 mice, which meant that the methylation changes at these three CpG sites were maintained.In conclusion, we found that paternal exposure to an HFD disrupted the methylation pattern of SETD2 in the sperm of F0 mice and resulted in perturbed SETD2 expression. Furthermore, the paternal high-fat diet influenced embryo apoptosis and development, possibly through the SETD2 pathway. The altered methylation of SETD2 in sperm induced by paternal HFD partially persisted in the sperm of the F1 generation, highlighting the role of SETD2 as an epigenetic carrier for paternal intergenerational and transgenerational inheritance.
父本高脂饮食（HFD）可改变精子DNA的表观遗传学，导致与肥胖相关的性状传递给后代。以往的研究主要集中在HFD诱导的印记基因DNA甲基化变化上，而忽略了非印记基因在此过程中的潜在作用。SETD2是一个重要的表观遗传调控基因，以其对环境应激的反应而闻名，但在高脂饮食诱导的表观遗传变化背景下，人们对它的了解仍然很少。在这里，我们研究了HFD导致的肥胖对父本SETD2在精子、囊胚期胚胎及后续发育过程中的表达和甲基化的影响，以确定SETD2在父本代际和跨代遗传中的变化。结果显示，喂食HFD两个月的小鼠睾丸和精子中SETD2表达显著增加。父本HFD显著改变了DNA甲基化水平，F0代小鼠精子中26个CpG位点中的20个发生了变化。父本高脂饮食增加了囊胚的凋亡指数并减少了其总细胞数，这与精子的DNA甲基化水平密切相关。在这26个CpG位点中，我们还发现F1代小鼠精子中有3个CpG位点发生了显著变化，这意味着这三个CpG位点的甲基化变化得以维持。总之，我们发现父本暴露于HFD会破坏F0代小鼠精子中SETD2的甲基化模式，并导致SETD2表达紊乱。此外，父本高脂饮食可能通过SETD2途径影响胚胎凋亡和发育。父本HFD诱导的精子中SETD2甲基化改变在F1代精子中部分持续存在，突出了SETD2作为父本代际和跨代遗传的表观遗传载体的作用。
