Transcriptional regulation in the innate immune system

Abstract

In cells of the innate immune system, the transcriptional response to a microbial stimulus is tailored to both the stimulus and cell type, suggesting the existence of highly sophisticated regulatory mechanisms. Early studies suggested that specificity is dictated by sets of differentially induced transcription factors that synergistically activate target genes containing their binding sites. However, recent studies have revealed additional interrelated regulatory layers, which are the topic of this article. In particular, individual transcription factors may require different post-translational modifications and coregulatory interactions to regulate different target genes. Furthermore, competence for induction is programmed at an early stage of development by factors involved in lineage commitment, and the architecture and chromatin structure of each promoter play critical roles in transcriptional specificity.

Figure 1

Acquisition of competence for transcriptional induction during development. The cell-type specificity of inducible genes appears to be strongly influenced by molecular events that occur during lineage commitment and/or early development. During early development, enhancers for inducible genes become associated with transcription factors that have long been implicated in lineage commitment and early development, including PU.1 [21**,22**]. Binding of PU.1 and other developmental regulators induces changes in chromatin structure and the acquisition of a histone H3K4me1 mark. Enhancers for some inducible genes are associated with transcription factors in pluripotent cells [29]. The molecular events that occur in pluripotent cells and during development may be necessary for transcriptional competence in stimulated mature cells. Upon stimulation, inducible transcription factors carry out additional interactions with the enhancers and promoters of inducible genes and promote additional changes in chromatin structure, culminating in transcriptional activation. The chromatin events required for transcriptional induction vary from gene to gene and are likely to contribute to selectivity of the transcriptional response to a stimulus.

Figure 2

Two distinct classes of promoters associated with inducible genes. Many inducible genes contain CpG-island promoters, which usually possess features of active chromatin in unstimulated cells. These features include high levels of histone H3K4me3, high levels of pre-associated RNA polymerase II, accessibility to restriction endonuclease cleavage, and low nucleosome density. The low nucleosome density may be due in part to the intrinsic instability of nucleosome assembled on CpG-island sequences. These features of active chromatin allow transcriptional induction in the absence of SWI/SNF-dependent nucleosome remodeling. CpG-island promoters are often associated with genes induced by a broad range of stimuli with little selectivity. In contrast, genes with low CpG promoters contain stable nucleosomes at their promoters, lack features of active chromatin in unstimulated cells, and often require nucleosome remodeling for their activation. The requirement for nucleosome remodeling provides an important barrier to transcriptional activation and confers a requirement for transcription factors that can recruit nucleosome remodeling complexes. IRF3 promotes nucleosome remodeling at several LPS-induced, remodeling-dependent primary response genes. Primary response genes that remain to be identified appear to be required for nucleosome remodeling at secondary response genes, as remodeling at these genes is dependent on new protein synthesis.