Epigenomic control of the innate immune response

Abstract

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.

Figure 1. General scheme for TLR-dependent regulation of gene expression

TLR dimers or heterodimers are activated by ‘danger’ (e.g., products of tissue injury) or ‘stranger’ (e.g., components of bacteria or viruses) signals. The liganded receptors couple to Myd88 and/or TRIF-dependent signal transduction pathways that function to activate latent transcription factors such as NFkB, AP-1 and interferon regulatory factors (IRFs). Upon activation, these factors bind to regulatory elements in target genes and positively regulate gene expression.

Figure 2. Epigenomic features of TLR-responsive promoters and enhancers under basal and activated conditions

A prototypic enhancer is illustrated at left and a prototypic promoter at right. Blue circles represent histone octomers. Lines emerging from the circles represent histone tails. LDTF; lineage determining transcription factor, GTF; general transcription factor, STDF; signal-dependent transcription factor. H3K4me1/2; histone H3 mono or di-methylated at lysine 4. H3K4me3; histone H3 trimethylated at lysine 4. H3K27me3; Histone H3 tri-methylated at lysine 27. H4K20me3; histone H4 trimethylated at lysine 20. H3K27ac; histone H3 acetylated at lysine 27.