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

Ruth Brignall,Suzanne Gaudet,Amy T Moody,Shibin Mathew

doi:10.3389/fimmu.2019.00609

Abstract

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 surmise that target gene transcription can broadly 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 place quantitative information that has been gathered about the NF-κB transcription regulation system into context and thus consider questions it answers, and questions it raises. 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.

Highlights

The nuclear factor-κB (NF-κB) family of transcription factors regulate the expression of genes that are crucial to a wide variety of biological processes, ranging from immune, stress, and inflammatory responses, to cell apoptosis
Because the ability of the RelA fusion proteins to induce transcription of target genes was verified in both the fluorescence recovery after photobleaching (FRAP) and single-molecule in vivo studies, these results suggest that long-lasting NF-κB binding may not be required for preinitiation complex assembly or for the activation of transcription
In the simple scenario that we depict (Figure Box 1A), we model the binding of transcription factors to their cognate sites on the genome as a simple adsorption process—where molecules bind to sites, unchanged

Summary

INTRODUCTION

The nuclear factor-κB (NF-κB) family of transcription factors regulate the expression of genes that are crucial to a wide variety of biological processes, ranging from immune, stress, and inflammatory responses, to cell apoptosis. High frequencies of transcription factor sampling have been observed at non-consensus sites, yet these interactions were shown to have no direct effect on transcription [42] This observation has revived ideas first proposed years ago, whereby a key part of the target search process is transcription factors making non-specific contacts with DNA and proceeding to slide or hop around the local chromatin environment until either a specific contact is formed, or contact and access to DNA is lost [43, 44]. This model could partially explain the large number of sites detected by static, end-point biochemical binding assays including ChIP-Seq studies, which appear to be non-functional. As we discuss in this review, there are many other nuances to abundance, affinity, and availability which will require more complex models to fully capture

Transcription factor Xcomp Competitor Y Binding Site

CONCLUSIONS