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

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. 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.已有研究证实，表观遗传特征（epigenetic features），如组蛋白修饰（histone modifications）与DNA甲基化（DNA methylation），与不同细胞类型中的基因表达密切相关。然而，目前尚不明确基因型变异如何影响表观遗传状态，也不清楚这类变异在多大程度上导致了遗传背景不同个体间的基因表达差异。本研究针对9个近交系小鼠品系的肝细胞，探究了可遗传表观遗传变异与基因表达之间的关联。其中8个近交系是多样性远交（Diversity Outbred，DO）小鼠的创始品系，第9个为DBA/2J；该品系与C57BL/6J均为BxD重组近交系小鼠群体的创始品系之一。我们检测了4种组蛋白修饰（H3K4me1、H3K4me3、H3K27me3与H3K27ac）以及DNA甲基化水平。借助ChromHMM工具，基于上述4种组蛋白修饰的检测结果，我们识别出14种代表不同修饰组合的染色质状态。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，不同品系间的表观遗传变异与基因表达存在相关性。在一个独立的DO小鼠群体中，我们通过推算局部表观遗传状态，验证了表观遗传状态与基因表达之间的对应关系。与之相反，我们未观察到近交品系间的DNA甲基化存在变异，且该修饰与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强烈影响，可能是表达数量性状基因座（expression Quantitative Trait Loci，eQTLs）发挥调控作用的主要途径之一。我们进一步证实，结合染色质状态的品系间变异与基因表达数据，可用于注释小鼠基因组的功能区域。最后，本研究提供了一个数据资源库，记录了遗传背景不同个体间的染色质状态变异情况。我们对9个近交系小鼠的肝细胞中的4种组蛋白修饰（H3K4me1、H3K4me3、H3K27ac及H3K4me3）进行了检测；同时在相同小鼠中分析了DNA甲基化模式与整体基因表达（bulk gene expression）水平，以探究遗传变异与表观遗传修饰变异及基因表达变异之间的关联。