Transcriptional Control by NF-κB: Elongation in Focus

• The transcription elongation stage is central in NF-κB regulation.
• Phosphorylation and acetylation of NF-κB p65 mediate P-TEFb recruitment via Brd4.
• This pathway is critical for activation of pro-inflammatory genes by NF-κB.
• Some anti-inflammatory genes are refractory to this pathway and regulated by DSIF.
• Differential regulation by elongation factors also has bearing on mRNA processing.

The NF-κB family of transcription factors governs the cellular reaction to a variety of extracellular signals. Following stimulation, NF-κB activates genes involved in inflammation, cell survival, cell cycle, immune cell homeostasis and more. This review focuses on studies of the past decade that uncover the transcription elongation process as a key regulatory stage in the activation pathway of NF-κB. Of interest are studies that point to the elongation phase as central to the selectivity of target gene activation by NF-κB. Particularly, the cascade leading to phosphorylation and acetylation of the NF-κB subunit p65 on serine 276 and lysine 310, respectively, was shown to mediate the recruitment of Brd4 and P-TEFb to many pro-inflammatory target genes, which in turn facilitate elongation and mRNA processing. On the other hand, some anti-inflammatory genes are refractory to this pathway and are dependent on the elongation factor DSIF for efficient elongation and mRNA processing. While these studies have advanced our knowledge of NF-κB transcriptional activity, they have also raised unresolved issues regarding the specific genomic and physiological contexts by which NF-κB utilizes different mechanisms for activation.