Considering Abundance, Affinity, and Binding Site Availability in the NF-κB Target Selection Puzzle

The NF-κB transcription regulation system governs a diverse set of responses to various cytokine stimuli. With tools from in vitro biochemical characterizations, to omics-based whole genome investigations, great strides have been made in understanding how NF-κB transcription factors control the expression of specific sets of genes. Nonetheless, these efforts have also revealed a very large number of potential binding sites for NF-κB in the human genome, and a puzzle emerges when trying to explain how NF-κB selects from these many binding sites to direct cell-type- and stimulus-specific gene expression patterns. In this review, we posit that target gene transcription can be thought of as a function of the nuclear abundance of the various NF-κB dimers, the affinity of NF-κB dimers for the regulatory sequence and the availability of this regulatory site. We use this framework to begin to make sense of the numbers – the quantitative information that has been gathered about the NF-κB transcription regulation system. We end with a brief discussion of some of the future prospects that new approaches could bring to our understanding of how NF-κB transcription factors orchestrate diverse responses in different biological contexts.