Epigenomic Landscape of Human Macrophages. 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.