Transcriptional control of inflammatory responses

Abstract

The inflammatory response requires the activation of a complex transcriptional program that is both cell-type- and stimulus-specific and involves the dynamic regulation of hundreds of genes. In the context of an inflamed tissue, extensive changes in gene expression occur in both parenchymal cells and infiltrating cells of the immune system. Recently, basic transcriptional mechanisms that control inflammation have been clarified at a genome scale, particularly in macrophages and conventional dendritic cells. The regulatory logic of distinct groups of inflammatory genes can be explained to some extent by identifiable sequence-encoded features of their chromatin organization, which impact on transcription factor (TF) accessibility and impose different requirements for gene activation. Moreover, it has become apparent that the interplay between TFs activated by inflammatory stimuli and master regulators exerts a crucial role in controlling cell-type-specific transcriptional outputs.

Figure 1.

DNA recognition specificities of TFs that control inflammatory gene expression. Representative examples are shown.

Figure 2.

The relationship between nucleosomes, lineage-determining TFs, and TFs activated by inflammatory stimuli. (Left) A poised enhancer in which nucleosome depletion and deposition of H3K4me1 is induced by Pu.1 during differentiation. In response to stimulation TFs, such as NF-κB, are recruited to the nucleosome-depleted area maintained by Pu.1. (Right) Latent enhancers are not detectable in terminally differentiated cells until a stimulus is delivered that activates TFs (such as Stat TFs) collaborating with Pu.1 to reconfigure local chromatin.