Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford, UK.
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Genome Biol. 2022 Jun 24;23(1):136. doi: 10.1186/s13059-022-02702-1.
Chromatin states and enhancers associate gene expression, cell identity and disease. Here, we systematically delineate the acute innate immune response to endotoxin in terms of human macrophage enhancer activity and contrast with endotoxin tolerance, profiling the coding and non-coding transcriptome, chromatin accessibility and epigenetic modifications.
We describe the spectrum of enhancers under acute and tolerance conditions and the regulatory networks between these enhancers and biological processes including gene expression, splicing regulation, transcription factor binding and enhancer RNA signatures. We demonstrate that the vast majority of differentially regulated enhancers on acute stimulation are subject to tolerance and that expression quantitative trait loci, disease-risk variants and eRNAs are enriched in these regulatory regions and related to context-specific gene expression. We find enrichment for context-specific eQTL involving endotoxin response and specific infections and delineate specific differential regions informative for GWAS variants in inflammatory bowel disease and multiple sclerosis, together with a context-specific enhancer involving a bacterial infection eQTL for KLF4. We show enrichment in differential enhancers for tolerance involving transcription factors NFκB-p65, STATs and IRFs and prioritize putative causal genes directly linking genetic variants and disease risk enhancers. We further delineate similarities and differences in epigenetic landscape between stem cell-derived macrophages and primary cells and characterize the context-specific enhancer activities for key innate immune response genes KLF4, SLAMF1 and IL2RA.
Our study demonstrates the importance of context-specific macrophage enhancers in gene regulation and utility for interpreting disease associations, providing a roadmap to link genetic variants with molecular and cellular functions.
染色质状态和增强子与基因表达、细胞身份和疾病相关。在这里，我们以人类巨噬细胞增强子活性为基础，系统地描述了内毒素诱导的急性先天免疫反应，并将其与内毒素耐受进行对比，分析了编码和非编码转录组、染色质可及性和表观遗传修饰。
我们描述了急性和耐受条件下的增强子谱，以及这些增强子与包括基因表达、剪接调控、转录因子结合和增强子 RNA 特征在内的生物学过程之间的调控网络。我们证明，在急性刺激时，绝大多数差异调节的增强子都受到耐受的影响，并且表达数量性状基因座、疾病风险变体和 eRNAs 在这些调节区域中富集，并与特定基因表达相关。我们发现，与内毒素反应和特定感染相关的特定 eQTL 以及与炎症性肠病和多发性硬化症的 GWAS 变体相关的特定差异区域具有特异性，同时还鉴定出一个与细菌感染 eQTL 相关的 KLF4 特定差异增强子。我们发现，在涉及转录因子 NFκB-p65、STATs 和 IRFs 的耐受差异增强子中存在富集，并优先考虑直接将遗传变异与疾病风险增强子联系起来的潜在因果基因。我们进一步描述了干细胞衍生的巨噬细胞和原代细胞之间在表观遗传景观上的相似性和差异，并对关键先天免疫反应基因 KLF4、SLAMF1 和 IL2RA 的特异性增强子活性进行了特征描述。
我们的研究表明了巨噬细胞特异性增强子在基因调控中的重要性，并为解释疾病相关性提供了一种方法，为将遗传变异与分子和细胞功能联系起来提供了一个路线图。
