Studies on PAF complex in the regulation of transcription and its role in the differentiation of Th17 cells

Abstract

To perform incredibly diverse biological activities with limited number of genes, organisms have developed complex temporal and spatial regulation mechanisms of gene expression. Dynamic regulation of RNA Polymerase II and its associated factors provide critical points of regulation in eukaryotic gene expression. PAF complex is an RNA polymerase II associated factor that controls diverse steps of gene expression. Although it is generally associated with active transcription, a repressive PAF complex has also been suggested. Furthermore, signal-specific function of PAF complex by interacting with signaling molecules is being reported recently. Using an immediate early gene, c-Fos, as a negatively regulated inducible target gene, I elucidated a novel mechanism of repressive PAF complex with signal specificity. PAF complex repressed c-Fos transcription by regulating the association of negative elongation factor, NELF which is important for RNA polymerase II pausing. Chromatin association of PAF complex was changed by a proinflammatory cytokine, interleukin-6 in a locus-specific manner. Involvement of PAF complex component, Ctr9 in interleukin-6 target gene expression suggested its possible role in the Th17 cell differentiation, where interleukin-6 is critical. I found that Ctr9 depletion in differentiating CD4 T cells enhanced the their differentiation into Th17 cells. Ctr9 expression was inhibited by interleukin-6 signal and its association with Il17 coding region was decreased during Th17 differentiation. This indicated the presence of a novel feed-forward loop in Il-17 transcriptional regulatory circuit. Although PAFc closely related to diverse cellular processes, such as cell cycle progression or development in mammals, its role in the mammalian immune system has not been addressed well yet. Here, I elucidated a molecular mechanism of repressive PAF complex under inflammatory condition. Based on potential of Ctr9 in interleukin-6 signaling, I also showed its physiological importance in the immune cell differentiation.