Variation in histone configurations correlates with gene expression across nine inbred strains of mice [RRBS]

It is well established that epigenetic features, such as histone modifications and DNA methylation, are associated with gene expression across cell types. However, it is not well known how variation in genotype affects epigenetic state, or to what extent such variation contributes to variation in gene expression across genetically distinct individuals. Here we investigated the relationship between heritable epigenetic variation and gene expression in hepatocytes across nine inbred mouse strains. Eight of the inbred strains were founders of the diversity outbred (DO) mice, and the ninth was DBA/2J, which, along with C57BL/6J, is one of the founders of the BxD recombinant inbred panel of mice. We surveyed four histone modifications, H3K4me1, H3K4me3, H3K27me3 and H3K27ac, as well as DNA methylation. We used ChromHMM to identify 14 chromatin states representing distinct combinations of the four measured histone modifications. We found that variation in chromatin state mirrored genetic variation across the inbred strains. Furthermore, epigenetic variation was correlated with gene expression across strains. The correspondence between epigenetic state and gene expression was replicated in an independent population of DO mice in which we imputed local epigenetic state. In contrast, we found that DNA methylation did not vary across inbred strains and was not correlated with variation in expression in DO mice. This work suggests that chromatin state is highly influenced by local genotype and may be a primary mode through which expression quantitative trait loci (eQTLs) are mediated. We further demonstrate that strain variation in chromatin state, paired with gene expression is useful for annotation of functional regions of the mouse genome. Finally, we provide a data resource that documents variation in chromatin state across genetically distinct individuals. Overall design: We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27ac, and H3K4me3) in hepatocytes nine inbred mouse strains. We also surveyed patterns of DNA methylation and bulk gene expression in the same mice to relate genetic variation to variation in epigenetic modifications and gene expression.

已有大量研究证实，组蛋白修饰（histone modifications）与DNA甲基化（DNA methylation）等表观遗传特征（epigenetic features）在不同细胞类型中均与基因表达（gene expression）密切相关。然而，基因型（genotype）的变异如何影响表观遗传状态（epigenetic state），以及此类变异在多大程度上促成遗传背景不同的个体间基因表达的差异，目前仍不甚明晰。本研究针对9种近交小鼠品系（inbred mouse strains）的肝细胞（hepatocytes）中的可遗传表观遗传变异与基因表达的关联展开探究。其中8种近交品系为多样性远交（diversity outbred, DO）小鼠的奠基品系，第9种为DBA/2J，其与C57BL/6J均为BxD重组近交群体（BxD recombinant inbred panel）小鼠的奠基品系。我们检测了4种组蛋白修饰——H3K4me1、H3K4me3、H3K27me3及H3K27ac，同时检测了DNA甲基化水平。借助ChromHMM，我们识别出由上述4种组蛋白修饰的不同组合构成的14种染色质状态（chromatin states）。研究发现，染色质状态的变异与各近交品系间的遗传变异高度吻合。此外，表观遗传变异与不同品系间的基因表达变异呈显著相关。表观遗传状态与基因表达的对应关系在一个独立的DO小鼠群体中得到了验证——我们在该群体中对局部表观遗传状态进行了推算。与之相反，我们未发现DNA甲基化在近交品系间存在变异，且其与DO小鼠的表达变异无相关性。本研究表明，染色质状态受局部基因型的影响极大，或为介导表达数量性状位点（expression quantitative trait loci, eQTLs）发挥作用的主要途径。我们进一步证实，结合基因表达的染色质状态品系变异，可用于注释小鼠基因组的功能区域。最后，我们提供了一个数据资源，该资源记录了遗传背景不同的个体间染色质状态的变异情况。总体实验设计：我们在9种近交小鼠品系的肝细胞中检测了4种组蛋白修饰（H3K4me1、H3K4me3、H3K27ac及H3K4me3），我们还在相同的小鼠中检测了DNA甲基化及批量基因表达（bulk gene expression）的模式，以探究遗传变异与表观遗传修饰及基因表达变异之间的关联。