Epigenomic control of the innate immune response

•TLR activation of latent transcription factors drives innate immune responses.•Massively parallel sequencing technologies permit global analysis of mechanisms.•Signal-dependent gene activation requires alterations in histone modifications.•Some histone modification-dependent mechanisms can be inhibited by drugs.•Epigenomic mechanisms may provide new targets for anti-inflammatory therapies.

Toll-like receptors (TLRs) play important roles in initiation of innate immune responses and promotion of pathological forms of inflammation. Recent technological advances have enabled the visualization of transcription factor binding and histone modifications in response to TLR signaling at genome-wide levels. Findings emerging from these studies are beginning to provide a picture of how signal-dependent transcription factors regulate the inflammatory response in a cell-specific manner by controlling the recruitment of nucleosome remodeling factors and histone modifying enzymes. Of particular interest, new small molecule inhibitors have been developed that influence inflammatory responses by altering the reading or erasure of histone modifications required for inflammatory gene activation. These findings suggest new approaches for treatment of inflammatory diseases.