Most transposable elements (TEs) in the mouse genome are heavily modified by DNA methylation and repressive histone modifications. However, a subset of TEs exhibit variable methylation levels in genetically identical individuals, and this is associated with epigenetically conferred phenotypic differences, environmental adaptability, and transgenerational epigenetic inheritance. The evolutionary origins and molecular mechanisms underlying interindividual epigenetic variability remain unknown. Using a repertoire of murine variably methylated intracisternal A-particle (VM-IAP) epialleles as a model, we demonstrate that variable DNA methylation states at TEs are highly susceptible to genetic background effects. Taking a classical genetics approach coupled with genome-wide analysis, we harness these effects and identify a cluster of KRAB zinc finger protein (KZFP) genes that modifies VM-IAPs in trans in a sequence-specific manner. Deletion of the cluster results in decreased DNA methylation levels and altered histone modifications at the targeted VM-IAPs. In some cases, these effects are accompanied by dysregulation of neighboring genes. We find that VM-IAPs cluster together phylogenetically and that this is linked to differential KZFP binding, suggestive of an ongoing evolutionary arms race between TEs and this large family of epigenetic regulators. These findings indicate that KZFP divergence and concomitant evolution of DNA binding capabilities are mechanistically linked to methylation variability in mammals, with implications for phenotypic variation and putative paradigms of mammalian epigenetic inheritance.

小鼠基因组中的大多数转座元件 (TE) 都受到 DNA 甲基化和抑制性组蛋白修饰的严重修饰。然而，一部分 TE 在基因相同的个体中表现出不同的甲基化水平，这与表观遗传赋予的表型差异、环境适应性和跨代表观遗传有关。个体间表观遗传变异的进化起源和分子机制仍然未知。使用小鼠可变甲基化脑池内 A 粒子 (VM-IAP) 表观等位基因库作为模型，我们证明 TE 的可变 DNA 甲基化状态非常容易受到遗传背景效应的影响。采用经典遗传学方法与全基因组分析相结合，我们利用这些效应并鉴定了一组 KRAB 锌指蛋白 (KZFP) 基因，它们以序列特异性方式反式修饰 VM-IAP。该簇的删除会导致 DNA 甲基化水平降低并改变目标 VM-IAP 上的组蛋白修饰。在某些情况下，这些影响伴随着邻近基因的失调。我们发现 VM-IAP 在系统发育上聚集在一起，并且这与差异的 KZFP 结合有关，表明 TE 和这个表观遗传调节因子大家族之间正在进行进化军备竞赛。这些发现表明，KZFP 分歧和 DNA 结合能力的伴随进化在机制上与哺乳动物的甲基化变异相关，对表型变异和哺乳动物表观遗传的假定范式具有影响。