The Diversity Outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression and, as such, are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a strain survey of epigenetic modifications in hepatocytes of the DO founders. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), as well as DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represents a distinct combination of the four histone modifications. We found that the epigenetic landscape is highly variable across the DO founders and is associated with variation in gene expression across strains. We found that epigenetic state imputed into a population of DO mice recapitulated the association with gene expression seen in the founders, suggesting that both histone modifications and DNA methylation are highly heritable mechanisms of gene expression regulation. We illustrate how DO gene expression can be aligned with inbred epigenetic states to identify putative cis-regulatory regions. Finally, we provide a data resource that documents strain-specific variation in the chromatin state and DNA methylation in hepatocytes across nine widely used strains of laboratory mice.

中文翻译：

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组蛋白构型的变化与九种近交系小鼠的基因表达相关

多样性远交 (DO) 小鼠及其近交创始人是广泛使用的人类疾病模型。然而，尽管这些小鼠的遗传多样性已得到充分记录，但它们的表观遗传多样性却没有。表观遗传修饰，例如组蛋白修饰和 DNA 甲基化，是基因表达的重要调节因子，因此是基因型和表型之间的关键机制联系。因此，在 DO 小鼠及其创建者中创建表观遗传修饰图谱是了解基因调控机制以及这种广泛使用的资源与疾病的联系的重要一步。为此，我们对 DO 创始人的肝细胞中的表观遗传修饰进行了菌株调查。我们调查了四种组蛋白修饰（H3K4me1、H3K4me3、H3K27me3 和 H3K27ac）以及 DNA 甲基化。我们使用 ChromHMM 识别了 14 个染色质状态，每个状态代表四种组蛋白修饰的独特组合。我们发现表观遗传景观在 DO 创始人之间存在很大差异，并且与品系之间基因表达的变化相关。我们发现，归咎于 DO 小鼠群体的表观遗传状态重现了与创始人中观察到的基因表达的关联，这表明组蛋白修饰和 DNA 甲基化都是基因表达调控的高度遗传机制。我们说明了如何将 DO 基因表达与近交表观遗传状态进行比对，以识别假定的顺式调控区域。最后，我们提供了一个数据资源，记录了九种广泛使用的实验室小鼠品系的染色质状态和肝细胞 DNA 甲基化的品系特异性变异。