The transcriptional control of genes involved in inflammation plays a critical role in host defense against pathogens, as well as in the 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 exciting strategy for the development of new therapies, including treatment of inflammation. Recently we discovered a novel mechanism that contributes to suppression of pro-inflammatory genes in macrophages. We identified a regulatory circuit where the bromodomain-containing protein BRD9 supports expression of a subset of non-coding RNAs, including the lncRNA RNU11 that suppresses TNF? and IL6 expression in LPS activated macrophages. In this proposal, we will address the role of BRD9 and BRD9- controlled lncRNA in regulation of the gene expression and inflammatory responses. We also describe an innovative methodology that utilizes the genome-wide CRISPR-mediated mutagenesis in human macrophages for identification of novel regulators of inflammation, including factors that contribute to the function of lncRNA.
We propose to address the mechanism and physiological significance of the novel negative regulators of 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. Recently, we discovered a novel mechanism that contributes to BCP-mediated suppression of pro- inflammatory genes in macrophages. We identified a novel regulatory circuit where the bromodomain- containing protein BRD9 supports expression of a subset of non-coding RNAs, including the lncRNA RNU11 that suppresses TNF? and IL6 expression in LPS 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 lncRNA function and address the significance of lncRNA 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 specific subsets of bromodomain-containing proteins.
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