An Expanded Interplay Network between NF-κB p65 (RelA) and E2F1 Transcription Factors: Roles in Physiology and Pathology

SIMPLE SUMMARY: Members of the NF-kappaB (κB) and the E2F transcription factor (TF) families regulate the expression of numerous genes controlling several biological processes, including cell proliferation and viability, metabolic pathways, pro-inflammatory, immune and stress-like responses, maintaining cell homeostasis, and physiology. While the NF-κB RelA/p65 and E2F1 TFs functions are quite distinct, they regulate the transcription of several common genes, but their interplay in target-gene promoters can either activate, blunt, or repress gene expression in different cell types affecting several processes, with physiological consequences. Using available genomics data, we showed that the RelA/p65 TF subunit binds to distal active enhancers, while the E2F1 TF binds to gene promoters. Further, RelA/p65 may attract and recruit E2F1 in gene promoters, acting potentially as a recruiting TF to properly control the transcription of target genes, a potential mechanism allowing for concerted actions of RelA/p65 and E2F1 in response to mitogenic, inflammatory, or genotoxic stimuli. ABSTRACT: Transcription Factors (TFs) are the main regulators of gene expression, controlling among others cell homeostasis, identity, and fate. TFs may either act synergistically or antagonistically on nearby regulatory elements and their interplay may activate or repress gene expression. The family of NF-κB TFs is among the most important TFs in the regulation of inflammation, immunity, and stress-like responses, while they also control cell growth and survival, and are involved in inflammatory diseases and cancer. The family of E2F TFs are major regulators of cell cycle progression in most cell types. Several studies have suggested the interplay between these two TFs in the regulation of numerous genes controlling several biological processes. In the present study, we compared the genomic binding landscape of NF-κB RelA/p65 subunit and E2F1 TFs, based on high throughput ChIP-seq and RNA-seq data in different cell types. We confirmed that RelA/p65 has a binding profile with a high preference for distal enhancers bearing active chromatin marks which is distinct to that of E2F1, which mostly generates promoter-specific binding. Moreover, the RelA/p65 subunit and E2F1 cistromes have limited overlap and tend to bind chromatin that is in an active state even prior to immunogenic stimulation. Finally, we found that a fraction of the E2F1 cistrome is recruited by NF-κΒ near pro-inflammatory genes following LPS stimulation in immune cell types.