Type I IFNs and TNF Cooperatively Reprogram Epigenomic Landscape of Human Macrophages to Promote Inflammatory Activation [RNA-seq]. Homo sapiens

Crossregulation of TLR responses by cytokines is essential for effective host defense, avoidance of toxicity, and homeostasis, but underlying mechanisms are not well understood. A comprehensive approach integrating RNA-seq, ChIP-seq and ATAC-seq digital footprinting showed that TNF and type I IFNs extensively remodel chromatin states in human macrophages to differentially regulate transcriptional induction of NF-κB, STAT, antiviral, and metabolic genes by LPS. IFN-α potentiated TNF inflammatory function by abrogating feedback silencing of inflammatory genes via priming of chromatin to enable robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings provide insights into epigenomic mechanisms by which cytokines reprogram inflammatory responses, and identify new functions and mechanisms of action of TNF and IFNs. Overall design: Analysis of transcriptional changes in human macrophages stimulated with or without TNF and LPS

细胞因子对Toll样受体（TLR）应答的交叉调控，对于高效宿主防御、毒性规避以及体内稳态维持不可或缺，但其潜在分子机制尚未得到充分阐释。本研究采用整合RNA测序（RNA-seq）、染色质免疫沉淀测序（ChIP-seq）与转座酶可及性染色质测序（ATAC-seq）数字足迹分析的综合研究策略，发现肿瘤坏死因子（TNF）与I型干扰素（type I IFNs）可在人类巨噬细胞中广泛重塑染色质状态，进而通过脂多糖（LPS）差异调控核因子κB（NF-κB）、信号转导与转录激活因子（STAT）、抗病毒相关及代谢相关基因的转录诱导。干扰素α（IFN-α）可通过预激活染色质，解除炎症基因的反馈性沉默，从而增强肿瘤坏死因子的炎症功能，使其可对微弱的上游信号产生强烈的转录应答。此类染色质调控机制在人类疾病中同样存在。本研究结果为细胞因子重编程炎症应答的表观基因组学机制提供了全新视角，并揭示了肿瘤坏死因子与干扰素的崭新功能及作用机制。整体实验设计：对经或未经肿瘤坏死因子与脂多糖刺激的人类巨噬细胞开展转录组变化分析。