One genome, many cell states: epigenetic control of innate immunity

•Chromatin dynamics regulate pattern, timing and magnitude of gene expression.•Signal transduction downstream of TLR4 regulate histones for inducible gene transcription.•Metabolic shifts and epigenetics of innate immune cells are intimately linked.•Chromatin dynamics enable memory of microbial exposure for tolerance or trained immunity.•Epigenetic therapies demonstrate promise for inflammatory disease. A hallmark of the innate immune system is its ability to rapidly initiate short-lived or sustained transcriptional programs in a cell-specific and pathogen-specific manner that is dependent on dynamic chromatin states. Much of the epigenetic landscape is set during cellular differentiation; however, pathogens and other environmental cues also induce changes in chromatin that can either promote tolerance or 'train' innate immune cells for amplified secondary responses. We review chromatin processes that enable innate immune cell differentiation and functional transcriptional responses in naive or experienced cells, in concert with signal transduction and cellular metabolic shifts. We discuss how immune chromatin mechanisms are maladapted in disease and novel therapeutic approaches for cellular reprogramming.