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.

在哺乳动物中，DNA甲基化模式是由各种类型的DNA甲基转移酶建立的，可以在细胞分裂过程中稳定传递，从而为表观遗传调控创造了范式，即使最初的触发信号消失了，它也可以介导基因表达的持久变化。尽管DNMT3A（一种甲基转移酶）的功能缺陷导致了异常的DNA甲基化模式，从而导致了哺乳动物的发育缺陷，但其过表达对组织基因表达和DNA甲基化模式的影响仍然不清楚。在这里，我们先前建立的hDNMT3A转基因大鼠模型以及mRNA测序和亚硫酸氢盐测序PCR用于分析hDNMT3A的影响随后研究了在组织转录组和甲基化组上的过表达，以及这种影响是否可以世代遗传。我们的结果表明，hDNMT3A的过表达可以诱导大鼠睾丸和大脑中明显的基因表达变化。更重要的是，这些变异中的36.02％和38.89％可以代际遗传给后代，而不会在大脑和睾丸中分别传递最初的内源性触发信号。此外，我们发现在其启动子和外显子中代际遗传的DNA甲基化变异可能是潜在的机制。与环境因素被动诱发的可遗传变异相比，这些变异是主动的由内源性表观遗传修饰因子诱导。该研究为主动诱导基因表达和DNA甲基化变异的内源性因子的表观遗传学提供了证据。但是，需要更多的研究来确定这些变异可以稳定遗传的世代数。