Cells of the immune system routinely respond to cues from their local environment and feedback to their surrounding through transient responses, choice of differentiation trajectories, plastic changes in cell state, and malleable adaptation to their tissue of residence. Genomic approaches have opened the way for comprehensive interrogation of such orchestrated responses. Focusing on genomic profiling of transcriptional and epigenetic cell state, we discuss how they are applied to investigate immune cells faced with various environmental cues. We highlight some of the emerging principles, on the role of dense regulatory circuitry, epigenetic memory, cell type fluidity, and reuse of regulatory modules, in achieving and maintaining appropriate responses to a changing environment. These provide a first step toward a systematic understanding of molecular circuits in complex tissues.
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