The transcriptional control of genes involved in inflammation plays a critical role in host defense against pathogens, as well as in development of inflammatory diseases. At the chromatin level, the gene activity is governed largely by post-translational nuclear protein modifications, including the protein lysine acetylation. The lysine acetylation of histones or non-histone proteins controls transcription by assembly of structurally and functionally distinct transcription complexes. The complex assembly relies on acetyl lysine interaction with the specialized bromodomain (BRD) that are present in numerous nuclear proteins. The BRD containing proteins (BCP) have recently emerged as promising targets for the development of specific interaction inhibitors, enabling a novel exiting strategy for the development of new therapies, including treatment of inflammation. This proposal addresses previously unknown role the BCP involvement in negative regulation of inflammation. We have identified a subfamily of anti-inflammatory BCP (aiBCP) that suppresses inflammatory gene expression in macrophages. In this proposal, we will address the mechanism of the aiBCP involvement in inflammatory gene regulation and aiBCP contribution to modulation of inflammatory processes in vivo. Our studies of the role of BRD in aiBCP function will facilitate development of novel immunomodulatory approaches that will target selectively BRD.
We propose to address the mechanism and physiological significance of the novel negative regulators of the inflammatory gene expression. We found that members of the structurally-related subfamily of the bromodomain containing proteins (BCP) suppress inflammatory gene expression in activated macrophages. Using in vitro and in vivo genetic approaches, as well as the chromatin and transcriptional analysis, we will identify the mechanism of the anti-inflammatory BCP (aiBCP) function and will address the significance of these proteins in inflammation in vivo. The proposed program will provide a fundamentally novel insight into transcriptional control of inflammation and will suggest novel approaches for the pharmacological control of inflammation by targeting the aiBCP.
| Tarakhovsky, Alexander; Prinjha, Rab K (2018) Drawing on disorder: How viruses use histone mimicry to their advantage. J Exp Med 215:1777-1787 |
| Dobenecker, Marc-Werner; Park, Joon Seok; Marcello, Jonas et al. (2018) Signaling function of PRC2 is essential for TCR-driven T cell responses. J Exp Med 215:1101-1113 |
| Razooky, Brandon S; Obermayer, Benedikt; O'May, Joshua Biggs et al. (2017) Viral Infection Identifies Micropeptides Differentially Regulated in smORF-Containing lncRNAs. Genes (Basel) 8: |
| von Schimmelmann, Melanie; Feinberg, Philip A; Sullivan, Josefa M et al. (2016) Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration. Nat Neurosci 19:1321-30 |
| Tough, David F; Tak, Paul P; Tarakhovsky, Alexander et al. (2016) Epigenetic drug discovery: breaking through the immune barrier. Nat Rev Drug Discov 15:835-853 |
| Yoshida, Hideyuki; Bansal, Kushagra; Schaefer, Uwe et al. (2015) Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells. Proc Natl Acad Sci U S A 112:E4448-57 |
| Sullivan, Josefa M; Badimon, Ana; Schaefer, Uwe et al. (2015) Autism-like syndrome is induced by pharmacological suppression of BET proteins in young mice. J Exp Med 212:1771-81 |
| Dobenecker, Marc-Werner; Kim, Jong Kyong; Marcello, Jonas et al. (2015) Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation. J Exp Med 212:297-306 |
| Schaefer, Anne; Sampath, Srihari C; Intrator, Adam et al. (2009) Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron 64:678-91 |
