Mechanisms by which noncoding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. Here, we evaluated effects of >50 million single-nucleotide polymorphisms and short insertions/deletions provided by five inbred strains of mice on the responses of macrophages to interleukin-4 (IL-4), a cytokine that plays pleiotropic roles in immunity and tissue homeostasis. Of >600 genes induced >2-fold by IL-4 across the five strains, only 26 genes reached this threshold in all strains. By applying deep learning and motif mutation analyses to epigenetic data for macrophages from each strain, we identified the dominant combinations of lineage-determining and signal-dependent transcription factors driving IL-4 enhancer activation. These studies further revealed mechanisms by which noncoding genetic variation influences absolute levels of enhancer activity and their dynamic responses to IL-4, thereby contributing to strain-differential patterns of gene expression and phenotypic diversity.

非编码遗传变异影响基因表达的机制仍然只是部分理解，但被认为是表型多样性和疾病风险的主要决定因素。在这里，我们评估了 5 种近交系小鼠提供的超过 5000 万个单核苷酸多态性和短插入/缺失对巨噬细胞对白细胞介素 4 (IL-4) 的反应的影响，白细胞介素 4 是一种在免疫和组织中发挥多效作用的细胞因子稳态。在 5 个菌株中由 IL-4 诱导 >2 倍的 >600 个基因中，只有 26 个基因在所有菌株中达到此阈值。通过对来自每个菌株的巨噬细胞的表观遗传数据应用深度学习和基序突变分析，我们确定了驱动 IL-4 增强子激活的谱系决定和信号依赖性转录因子的主要组合。