Department of Genetics, University of Cambridge, CB2 3EH Cambridge, United Kingdom.
The Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 2020 Dec 8;117(49):31290-31300. doi: 10.1073/pnas.2017053117. Epub 2020 Nov 25.
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 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.
大多数小鼠基因组中的转座元件（TEs）都被 DNA 甲基化和抑制性组蛋白修饰所修饰。然而，一小部分 TEs 在遗传上相同的个体中表现出可变的甲基化水平，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遗传有关。个体间表观遗传变异性的进化起源和分子机制仍然未知。我们使用一系列小鼠可变甲基化内体 A 粒子（VM-IAP）表观等位基因作为模型，证明了 TEs 中可变的 DNA 甲基化状态极易受到遗传背景的影响。通过采用经典遗传学方法结合全基因组分析，我们利用这些效应并鉴定出一组 KRAB 锌指蛋白（KZFP）基因，这些基因以序列特异性的方式修饰 VM-IAPs。该基因簇的缺失导致靶向 VM-IAP 上的 DNA 甲基化水平降低和组蛋白修饰改变。在某些情况下，这些效应伴随着邻近基因的失调。我们发现 VM-IAPs 在系统发育上聚集在一起，这与不同的 KZFP 结合有关，提示 TE 和这个大型表观遗传调控因子家族之间正在进行一场进化军备竞赛。这些发现表明，KZFP 的分化以及与 DNA 结合能力的协同进化与哺乳动物中的甲基化变异性在机制上有关，这对表型变异和哺乳动物表观遗传遗传的潜在范例具有影响。
