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反转录转座子的序列特征允许表观遗传变异性。

Sequence features of retrotransposons allow for epigenetic variability.

机构信息

Department of Diabetes Complications and Metabolism, Beckman Research Institute, Duarte, United States.

Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, United States.

出版信息

Elife. 2021 Oct 20;10:e71104. doi: 10.7554/eLife.71104.

DOI:10.7554/eLife.71104
PMID:34668484
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8555987/
Abstract

Transposable elements (TEs) are mobile genetic elements that make up a large fraction of mammalian genomes. While select TEs have been co-opted in host genomes to have function, the majority of these elements are epigenetically silenced by DNA methylation in somatic cells. However, some TEs in mice, including the Intracisternal A-particle (IAP) subfamily of retrotransposons, have been shown to display interindividual variation in DNA methylation. Recent work has revealed that IAP sequence differences and strain-specific KRAB zinc finger proteins (KZFPs) may influence the methylation state of these IAPs. However, the mechanisms underlying the establishment and maintenance of interindividual variability in DNA methylation still remain unclear. Here, we report that sequence content and genomic context influence the likelihood that IAPs become variably methylated. IAPs that differ from consensus IAP sequences have altered KZFP recruitment that can lead to decreased KAP1 recruitment when in proximity of constitutively expressed genes. These variably methylated loci have a high CpG density, similar to CpG islands, and can be bound by ZF-CxxC proteins, providing a potential mechanism to maintain this permissive chromatin environment and protect from DNA methylation. These observations indicate that variably methylated IAPs escape silencing through both attenuation of KZFP binding and recognition by ZF-CxxC proteins to maintain a hypomethylated state.

摘要

转座元件 (TEs) 是一类可移动的遗传元件，它们构成了哺乳动物基因组的很大一部分。虽然一些 TEs 已经被宿主基因组“借用”来发挥作用，但这些元件中的大多数在体细胞中通过 DNA 甲基化被沉默。然而，一些小鼠中的 TEs，包括逆转录转座子的内体 A 粒子 (IAP) 亚家族，已经显示出 DNA 甲基化在个体间存在差异。最近的研究表明，IAP 序列差异和特定于品系的 KRAB 锌指蛋白 (KZFPs) 可能影响这些 IAP 的甲基化状态。然而，DNA 甲基化个体间变异性的建立和维持机制仍不清楚。在这里，我们报告序列内容和基因组环境会影响 IAP 成为可变甲基化的可能性。与共识 IAP 序列不同的 IAP 具有改变的 KZFP 募集，当接近组成型表达的基因时，可能导致 KAP1 募集减少。这些可变甲基化的基因座具有高 CpG 密度，类似于 CpG 岛，并且可以被 ZF-CxxC 蛋白结合，为维持这种允许的染色质环境和防止 DNA 甲基化提供了一种潜在的机制。这些观察结果表明，可变甲基化的 IAP 通过降低 KZFP 结合和 ZF-CxxC 蛋白的识别来逃避沉默，以维持低甲基化状态。

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