NF-κB and chromatin: ten years on the path from basic mechanisms to candidate drugs

Abstract

Release of nuclear factor κΒ (NF-κB) dimers from the inhibitors of NF-κΒ (IκBs) and their subsequent nuclear translocation are only the initial events leading to the induction of NF-κB-regulated genes. Once in the nucleus, NF-κB dimers must gain access to their cognate sites in target genes. While some sites are found in a constitutively accessible state, many others are associated with nucleosomal histones in a manner that prevents NF-κB binding. Binding to such sites requires specific chromatin remodeling events driven by functionally cooperating transcription factors. Ten years of research on the complex interplay between chromatin and NF-κB led to some major successes, most notably the identification of the specific sequence features or trans-acting factors controlling the state of accessibility of κB sites, as well as the dissection of the mechanisms and players involved in the opening of occluded sites. Moreover, attempts at identifying mechanism-based compounds that inhibit the activation of selected subsets of NF-κB-dependent genes acting on chromatin-regulated transitions are starting to give initial promising results in preclinical tests.