Autophagy involves a long process that starts with signaling, followed by LC3 protein lipidation and autophagosome formation, leading to fusion with lysosomes and ubiquitin mediated protein degradation. Each of the above processes is controlled by autophagy specific genes conserved from yeast to humans. Our initial microarray and ChIP-on chip analyses indicated that some of autophagy related genes are downregulated in IRF8-/- DCs relative to IRF8+/+ DC. The follow-up study confirmed that IRF8 is required for expression of a large number of autophagy specific genes in both macrophages and DC. Some of these genes are induced by IFN and IRF8 bound to the upstream promoter regions. Consistent with these findings, IRF8 -/- macrophages were defective in lipidation mediated conversion of LC3 and autophagosome formation. These results raise the possibility that IRF8 utilizes autophagy to eliminate certain pathogens including TB. IRF8 is induced by IFNan inflammatory cytokine and ligand binding of pathogen recognition receptors and plays an essential role in elimination of various pathogens. In addition to IFNIL17 is an inflammatory cytokine produced by T cells, which mobilizes neutrophils (granulocyes). Increased IL17 is associated with various autoimmune diseases, including multiple sclerosis and inflammatory colitis. While IL12 is important for activation of IFNproducing T cells (Th1), TGFand IL6 are required for IL17 producing T cells (Th17).We obtained evidence that IRF8 is required for TGF/IL6 activation of Th17 cells. Furthermore, Survival and expansion of Th17 cells is shown to be dependent on IL23, a cytokine related to IL12. Similar to IL12, IL23 depends on IL12p40, whose expression depends on IRF8. These results collectively indicate that IRF8 critically contributes to Th17 based inflammation. Transcriptionally active genes are embedded in chromatin that is dynamically exchanged, whereas silenced genes are surrounded by more stable chromatin. Chromatin environment influences transcription and constitutes part of epigenetic regulation. We are interested in BRD4, a chromatin binding protein associated with transcribed genes. We are also interested in histone H3.3, the variant histone, selectively associated with actively expressed genes. BRD4 is a 200 kDa nuclear protein carrying two tandem bromodomains through which it binds to acetylated chromatin. BRD4 also interacts with the elongation factor, P-TEFb and regulates transcription of many genes, including those induced by external stimuli. BRD4 is implicated for transcriptional memory across cell division, because it stays on condensed chromosomes during mitosis and affects gene expression in the daughter cells. Despite the close structural similarity with the standard H3.1 and H3.2, histone H3.3 has an extraordinary property, in that it is incorporated into nucleosomes and DNA as genes are transcribed. In contrast, H3.1 and H3.2 and other standard core histones are incorporated into nucleosomes during DNA replication. The dichotomy between H3.3 vs H3.1/2 highlights distinct chromatin activities during replication and transcription. Although there is increasing recognition about the importance of transcription-coupled histone exchange, the process and its physiological significance remains obscure. Our goal is to elucidate the activity of BRD4 and histone H3.3 in the context of transcriptional activation and epigenetic memory.

Project Start
Project End
Budget Start
Budget End
Support Year
27
Fiscal Year
2013
Total Cost
$937,804
Indirect Cost
City
State
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