Transgenerational inheritance of obesity correlates with transmission of epigenetic alterations in the Fto gene [ATAC-seq]

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 Analysis of transcription factor binding by ATAC-seq