Hierarchies of NF-κB target-gene regulation

Abstract

Members of the NF-κB family of transcription factors function as dominant regulators of inducible gene expression in almost all cell types in response to a broad range of stimuli, with particularly important roles in coordinating both innate and adaptive immunity. This review summarizes the present knowledge and recent progress toward elucidating the numerous regulatory layers that confer target-gene selectivity in response to an NF-κB-inducing stimulus.

Figure 1

Contributors to selectivity of the NF-κB response. Selectivity of the NF-κB response is regulated by multiple events that take place during the development of a responsive cell type, and by a broad range of events that act following stimulation.

Figure 2

Enhancers for NF-κB target genes may acquire competence for activation at early stages of development. The diagram depicts events that appear to occur at enhancers for NF-κB target genes during development. Enhancers for some inducible genes appear to be associated with transcription factors in pluripotent cells, which may keep CpG dinucleotides in an unmethylated state and serve as placeholders during the earliest stages of development. During early stages of development, key transcription factors involved in lineage commitment, specification, or development, such as PU.1 in myeloid- and B-lineage cells, appear to bind the enhancers and induce local chromatin changes (histone H3K4me1 and nucleosome repositioning) that may confer competence for transcriptional activation in differentiated cells. As the differentiated cell responds to a stimulus, NF-κB and other inducible transcription factors bind the enhancer and recruit essential co-activators, such as p300. The enhancer complex is then thought to interact with the gene's promoter, which also binds constitutive, lineage-specific, and inducible transcription factors, including NF-κB, thereby promoting the cascade of events that culminates in transcription initiation and elongation.