Transgenerational inheritance of obesity correlates with transmission of epigenetic alterations in the Fto gene [Hi-C]. Transgenerational inheritance of obesity correlates with transmission of epigenetic alterations in the Fto gene [Hi-C]

Evidence suggestive of inter- and transgenerational inheritance of epiphenotypes in mammals has been reported extensively. Numerous studies suggest a link between parental environments and a variety of effects in the offspring. For example, exposure of laboratory animals or humans to endocrine disrupting compounds leads to increased reproductive dysfunction, cancer, obesity, diabetes, and behavioral disorders. However, the mechanisms by which these epiphenotypes are transmitted between the exposed and subsequent generations through the paternal germline remain poorly understood. Here we show that exposure of pregnant mouse females during E7.5-E13.5 to bisphenol A (BPA) results in obesity in the F2 progeny. This epiphenotypes can be transmitted through the male and female germlines up to the F6 generation and disappears in F7. Analysis of chromatin changes in the sperm of the F1 generation reveals a widespread increase in chromatin accessibility at binding sites for CTCF, FoxA1, ESR1, ESR2, AR, and Pparg. Changes in CTCF/cohesin are accompanied by alterations in 3D organization that affect enhancer-promoter interactions. Comparison of the transmission of obesity with alterations in the binding of these transcription factors points to the activation of an enhancer in an intron of the Fto gene as the cause of transgenerational transmission of obesity. The results suggest that both genetic and epigenetic alterations of the same gene can lead to adverse effects on human health. Overall design: Analysis of transcription factors in sperm.

哺乳动物表观表型（epiphenotype）的代间与跨代遗传相关证据已被广泛报道。大量研究表明，亲本所处环境与子代的多种表型效应存在关联。例如，实验动物或人类暴露于内分泌干扰化合物（endocrine disrupting compounds）后，生殖功能障碍、癌症、肥胖、糖尿病及行为障碍的发病风险会显著升高。然而，这些表观表型通过父系生殖细胞系在暴露个体与后续世代间传递的具体机制仍未得到充分阐明。本研究显示，对妊娠雌鼠在胚胎发育第7.5天至13.5天（E7.5-E13.5）阶段施加双酚A（bisphenol A, BPA）暴露，可使F2代子代出现肥胖表型。该表观表型可通过雌雄生殖细胞系传递至F6代，并于F7代消失。对F1代小鼠精子的染色质变化进行分析后发现，CTCF、FoxA1、ESR1、ESR2、AR及Pparg的结合位点区域的染色质可及性普遍升高。CTCF/黏连蛋白的变化伴随3D基因组组织结构的改变，进而影响增强子-启动子的相互作用。通过对比肥胖表型的传递情况与上述转录因子结合的变化，研究证实Fto基因内含子区域的一个增强子被激活，这正是肥胖跨代传递的致病机制。本研究结果表明，同一基因的遗传与表观遗传改变均可对人类健康产生不良影响。整体实验设计：对精子中的转录因子进行分析。