Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4 [ChIP-seq]. Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4 [ChIP-seq]

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. Overall design: ChIP-seq for BMDMs (bone marow-derived macrophages) from five mouse strains with IL-4 treatment **Please note that [1] each processed data (linked as Series supplementary files) was generated from multiple samples as indicated in the corresponding sample description field. [2] raw data for human sample is not provided due to privacy concerns.

非编码遗传变异调控基因表达的具体机制目前仍未完全阐明，但该过程被认为是表型多样性与疾病风险的关键决定因素。本研究针对5个近交系小鼠（inbred strains of mice）提供的超5000万条单核苷酸多态性（single-nucleotide polymorphisms, SNP）与短插入缺失（short insertions/deletions, indel），分析其对巨噬细胞（macrophages）应答白细胞介素-4（interleukin-4, IL-4）的影响——IL-4是一种在免疫与组织稳态中发挥多效性作用的细胞因子。在5个品系中均被IL-4诱导上调2倍以上的600余个基因中，仅26个基因在所有品系中均达到该表达阈值。通过对各品系巨噬细胞的表观遗传数据开展深度学习（deep learning）与基序突变分析（motif mutation analyses），我们鉴定出调控IL-4增强子（enhancer）激活的谱系决定性转录因子与信号依赖性转录因子的优势组合模式。本研究进一步阐明了非编码遗传变异如何影响增强子活性的绝对水平及其对IL-4的动态应答，进而促成不同品系间基因表达模式与表型多样性的差异。研究设计：对经IL-4处理的5个小鼠品系的骨髓源巨噬细胞（bone marrow-derived macrophages, BMDMs）进行染色质免疫共沉淀测序（chromatin immunoprecipitation sequencing, ChIP-seq）。请注意：[1] 如对应样本描述字段所示，每一份处理后数据（以系列补充文件链接形式提供）均由多个样本生成；[2] 出于隐私保护考量，未提供人类样本的原始数据。