Abstract
Activation of the transcription factor NF-κB elicits an individually tailored transcriptional response in order to meet the particular requirements of specific cell types, tissues, or organs. Control of the induction kinetics, amplitude, and termination of gene expression involves multiple layers of NF-κB regulation in the nucleus. Here we discuss some recent advances in our understanding of the mutual relations between NF-κB and chromatin regulators also in the context of different levels of genome organization. Changes in the 3D folding of the genome, as they occur during senescence or in cancer cells, can causally contribute to sustained increases in NF-κB activity. We also highlight the participation of NF-κB in the formation of hierarchically organized super enhancers, which enable the coordinated expression of co-regulated sets of NF-κB target genes. The identification of mechanisms allowing the specific regulation of NF-κB target gene clusters could potentially enable targeted therapeutic interventions, allowing selective interference with subsets of the NF-κB response without a complete inactivation of this key signaling system.
Highlights
A major question in the field is how this dynamics relates to the different levels of chromatin or pathological conditions
These chromosome territories can be further partitioned into distinct compartments, which are enriched for transcriptionally active euchromatin (A compartments) or transcriptionally repressed heterochromatin (B compartments), respectively [29]
Histone variants for NF-κB signaling, as they strongly contribute to chromatin dynamics
Summary
The nuclear factor kappa B (NF-κB) signaling module is a complex and highly interconnected molecular network, with important functions in, probably, all nucleated cells [1]. The nuclear response is highly regulated at multiple levels, to allow precise control of all parameters relevant to NF-κB-driven gene expression as a prerequisite for an appropriate biological response This involves the physical interaction of NF-κB subunits with many nuclear proteins, as visualized by an interaction network of the subunits with further proteins, using the STRING database (https://string-db.org/, accessed on 4 March 2021) (Figure 1B). While a pulsed stimulus results in a single peak of strongly activated gene expression, persistent or recurrent exposure to high concentrations of NF-κB triggers an oscillatory NF-κB response, as it is reflected by periodically elevated levels of TNFα in rheumatoid arthritis or IL-1β in chronic gout arthritis [16].
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