KRAB zinc finger protein diversification drives mammalian interindividual methylation variability.
KRAB zinc finger protein diversification drives mammalian interindividual methylation variability.
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DOI：
10.1073/pnas.2017053117
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发表时间：
2020-12-08
影响因子：
11.1
通讯作者：
Ferguson-Smith AC
中科院分区：
文献类型：
--
作者：
Bertozzi TM;Elmer JL;Macfarlan TS;Ferguson-Smith AC
转座因子（TE）是具有移动潜力的重复序列，导致遗传多样性。为了限制这一点，小鼠中的大多数TE都通过DNA甲基化进行了严重的表观遗传修饰。然而，少数TE表现出个体间不同的可变甲基化水平，并赋予表观遗传而非遗传对表型的影响。这背后的机制仍然未知。我们报告了一个多态性簇的KRAB锌指蛋白（KZFPs）负责表观遗传特性的这些甲基化的TE的鉴定，与集群的删除深刻影响其DNA甲基化和相邻基因的表达。我们建议，快速KZFP分歧的基础上可变的表观遗传状态在哺乳动物中，与表观遗传赋予的表型差异内和跨代的个人之间的影响。小鼠基因组中的大多数转座因子（TE）都受到DNA甲基化和抑制性组蛋白修饰的严重修饰。然而，在遗传上相同的个体中，一部分TE表现出可变的甲基化水平，这与表观遗传学赋予的表型差异、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。使用一个剧目的小鼠脑池内A-颗粒（VM-IAP）表观等位基因作为一个模型，我们表明，在TE的可变DNA甲基化状态是非常容易受到遗传背景的影响。采用经典的遗传学方法，结合全基因组分析，我们利用这些影响，并确定了一组KRAB锌指蛋白（KZFP）基因，以序列特异性的方式修改VM-IAP的反式。该簇的缺失导致靶向VM-IAP处DNA甲基化水平降低和组蛋白修饰改变。在某些情况下，这些影响伴随着相邻基因的失调。我们发现，VM-IAPs集群在一起的遗传学，这是联系在一起的差异KZFP结合，这表明正在进行的进化军备竞赛之间的TE和这个大家庭的表观遗传调节。这些研究结果表明，KZFP分歧和DNA结合能力的伴随进化与哺乳动物中的甲基化变异性有机械联系，对表型变异和哺乳动物表观遗传的推定范式有影响。
Transposable elements (TEs) are repetitive sequences with potential to mobilize, causing genetic diversity. To restrict this, most TEs in the mouse are heavily epigenetically modified by DNA methylation. However, a few TEs exhibit variable methylation levels that differ between individuals and confer an epigenetic, rather than genetic, influence on phenotype. The mechanism underlying this remains unknown. We report the identification of a polymorphic cluster of KRAB zinc finger proteins (KZFPs) responsible for the epigenetic properties of these variably methylated TEs, with deletion of the cluster profoundly influencing their DNA methylation and expression of adjacent genes. We propose that rapid KZFP divergence underlies variable epigenetic states in mammals, with implications for epigenetically conferred phenotypic differences between individuals within and across generations. 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.
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影响因子：
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作者：
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通讯作者：
Ferguson-Smith AC