Overexpression of human-derived DNMT3A induced intergenerational inheritance of DNA methylation and gene expression variations in rat brain and testis

In mammals, DNA methylation patterns are established by various types of DNA methyltransferases and can be stably passed on during cell division, thus creating a paradigm for epigenetic regulation that can mediate long-lasting changes in gene expression even when the initial triggering signal has disappeared. Although functional deficiency of DNMT3A, one of the methyltransferases, leads to abnormal DNA methylation patterns that result in developmental deficits in mammals, the impacts of its overexpression on tissue gene expression and DNA methylation patterns remain unclear. Here, our previously established hDNMT3A transgenic rat model and mRNA sequencing and bisulphite sequencing PCR were used to analyse the impact of hDNMT3A overexpression on tissue transcriptome and methylome, and whether the impact could be inherited intergenerationally was subsequently investigated. Our results revealed that the overexpression of hDNMT3A could induce notable gene expression variations in rat testis and brain. More importantly, 36.02% and 38.89% of these variations could be intergenerationally inherited to offspring without the transmission of the initial endogenic trigger in the brain and testis, respectively. Furthermore, we found that intergenerationally inherited DNA methylation variations in their promoters and exons could be the underlying mechanism. Compared with inheritable variations that were passively induced by environmental factors, these variations were actively induced by endogenous epigenetic modifiers. This study provided evidence for the epigenetic inheritance of endogenous factors that actively induce gene expression and DNA methylation variations; however, more studies are needed to determine the number of generations that these variations can be stably inherited.