IL-1β–specific recruitment of GCN5 histone acetyltransferase induces the release of PAF1 from chromatin for the de-repression of inflammatory response genes

Abstract

To determine the functional specificity of inflammation, it is critical to orchestrate the timely activation and repression of inflammatory responses. Here, we explored the PAF1 (RNA polymerase II associated factor)-mediated signal- and locus-specific repression of genes induced through the pro-inflammatory cytokine interleukin (IL)-1β. Using microarray analysis, we identified the PAF1 target genes whose expression was further enhanced by PAF1 knockdown in IL-1β–stimulated HepG2 hepatocarcinomas. PAF1 bound near the transcription start sites of target genes and dissociated on stimulation. In PAF1-deficient cells, more elongating RNA polymerase II and acetylated histones were observed, although IL-1β–mediated activation and recruitment of nuclear factor κB (NF-κB) were not altered. Under basal conditions, PAF1 blocked histone acetyltransferase general control non-depressible 5 (GCN5)-mediated acetylation on H3K9 and H4K5 residues. On IL-1β stimulation, activated GCN5 discharged PAF1 from chromatin, allowing productive transcription to occur. PAF1 bound to histones but not to acetylated histones, and the chromatin-binding domain of PAF1 was essential for target gene repression. Moreover, IL-1β–induced cell migration was similarly controlled through counteraction between PAF1 and GCN5. These results suggest that the IL-1β signal-specific exchange of PAF1 and GCN5 on the target locus limits inappropriate gene induction and facilitates the timely activation of inflammatory responses.

Induction of NKG2D Ligands on Solid Tumors Requires Tumor-Specific CD8+ T Cells and Histone Acetyltransferases

“…Nuclear factor-κB (NF-κB) cooperates with GCN5/PCAF complex to regulate the expression of multiple genes (44–46), and NF-κB also serves as a regulator of NKG2D ligands (47). Hence, it is possible that inflammatory cytokines activate NF-κB, which in turn recruits GCN5/PCAF to upregulate NKG2D ligands.…”

Transcriptional Regulator CTR9 Inhibits Th17 Differentiation via Repression of IL-17 Expression

“…It is usually found associated with the coding regions of the actively transcribing genes (40,41) and hence suggested as an activator of transcription. However, there are also a handful of reports proposing a negative role of PAFc in transcription (42)(43)(44)(45)(46). Both Paf1 and Ctr9 repress the SER3 gene by reducing nucleosome occupancy and recruiting of Spt16 (43).…”

Cytoplasmic parafibromin/hCdc73 targets and destabilizes p53 mRNA to control p53-mediated apoptosis

“…Chromatin IP was performed as described previously with some modifications 25 . Briefly, 4 Â 10 7 cells were cross-linked with 1% formaldehyde and lysed in cell lysis buffer (20 mM Tris-HCl, pH 8.0, 85 mM KCl, 0.5% NP-40, with protease inhibitors).…”

“…To understand how p53 levels were increased in hCdc73-deficient cells, we first examined whether hCdc73 repressed the transcription of p53, because it has been reported that PAFc represses immediate early genes and interleukin-1-inducible PLAU genes 25 . p53 gene transcription was active under basal conditions, and relatively strong RNA Pol II-Ser2P occupancy was detected at the coding region of the p53 locus in control cells (Fig.…”