title: 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.
authors.affiliation: Division of Molecular and Life Sciences, Department of Life Sciences, Pohang University of Science and Technology POSTECH, Pohang 790-784, Republic of Korea.
authors.forename: Nari
authors.initials: N
authors.lastname: Kim
authors.forename: Hwa-Young
authors.initials: HY
authors.lastname: Sun
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Youn
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Yoo
mesh_terms: D000107:Acetylation; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002843:Chromatin / Q000378:metabolism*; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D061805:Transcription Elongation, Genetic; D014157:Transcription Factors; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; D051548:Histone Acetyltransferases; D006657:Histones; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D016328:NF-kappa B; D009687:Nuclear Proteins; D014157:Transcription Factors; D014568:Urokinase-Type Plasminogen Activator; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C501972:PAF1 protein, human; C547921:RNA polymerase II associated factor 1, mouse