Regulation of the toll-like receptor-induced transcriptional program

Inducible transcription occurs through a series of regulated events commencing with ligand binding to the receptor and resulting in target gene transcription. The events leading to transcription can be divided into those that promote signal transduction, and therefore affect all target genes similarly, and those that result in gene-specific expression. Given the diversity of functional gene products induced by some receptors, we hypothesized that gene-specific regulatory mechanisms should govern the differential expression of functional classes of genes. We addressed this question in two settings, induction under normal physiological conditions and control under pathological conditions of chronic stimulation. First, we show that the 'rate-limiting' step in the pathway to transcription is different for genes induced downstream of a common receptor. This has significant ramifications for the rapidity and specificity of gene induction. We then show that genes are independently controlled during chronic stimulation based on their function. In both settings, expression patterns are associated with gene-specific modifications to the chromatin structure that facilitate or suppress transcription. Finally, we explore how differences in chromatin structure are established and how transcription is regulated in light of these differences.