Lim, E.J., Lu, T.X., Blanchard, C. & Rothenberg, M.E. Epigenetic regulation of the IL-13-induced human eotaxin-3 gene by CREB-binding protein-mediated histone 3 acetylation. J. Biol. Chem. 286, 13193-13204
The etiology of a variety of chronic inflammatory disorders has been attributed to the interaction of genetic and environmental factors. Herein, we identified a link between epigenetic regulation and IL-13-driven eotaxin-3 in the pathogenesis of chronic allergic inflammation. We first demonstrated that the cAMP-responsive element (CRE) site in the eotaxin-3 promoter affects IL-13-induced eotaxin-3 promoter activity. Furthermore, the CRE-binding protein-binding protein (CBP), a histone acetyltransferase, induced base-line and IL-13-induced eotaxin-3 promoter activity. Additionally, IL-13 treatment promoted global histone 3 acetylation as well as the formation of a complex containing CBP and STAT6 and the subsequent acetylation of histone 3 at the eotaxin-3 promoter. CBP gene silencing decreased IL-13-induced transcription of eotaxin-3. Conversely, inhibition of histone deacetylation increased IL-13-induced eotaxin-3 production. Clinical studies demonstrated markedly increased global acetylation of histone 3 in the inflamed tissue of patients with allergic inflammation. Collectively, these results identify an epigenetic mechanism involving CBP and chromatin remodeling in regulating IL-13-induced chemokine transcription.
[Show abstract][Hide abstract] ABSTRACT: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus that is compounded by both genetic predisposition and aberrant responses to environmental antigens, particularly those that are food derived. Data have indicated a unique transcriptional response in vivo that defines EoE and that appears to be partially attributable to the T(H)2 cytokine IL-13. Moreover, a number of genetic risk variants in proinflammatory and epithelial cell genes associate with EoE susceptibility, demonstrating novel heritable mechanisms that contribute to disease risk. Here we discuss recent advances in our understanding of the intrinsic (genetic) and extrinsic (environmental) components that illustrate the complex nature of EoE.
The Journal of allergy and clinical immunology 05/2011; 128(1):23-32; quiz 33-4. DOI:10.1016/j.jaci.2011.03.046 · 11.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The development of allergic inflammation requires the orchestration of gene expression from the inflamed tissue and from the infiltrating immune cells. Since many of the cytokines that promote allergic inflammation signal through hematopoietin family receptors, the Signal Transducer and Activator of Transcription (STAT) family have obligate roles in pro-allergic cytokine-induced gene regulation in multiple cell types. In this review, we summarize work defining the contribution of each of the STAT family members to the development of allergic inflammation, using data from mouse models of allergic inflammation, studies on patient samples and correlations with single nucleotide polymorphisms in STAT genes.
[Show abstract][Hide abstract] ABSTRACT: Histoneacetyltransferases (HATs) are promising epigenetic drug targets and are involved in the pathogenesis of a wide range of diseases. We carried out a virtual screening based on inhibitors of serotonin N-acetyltransferase and identified novel inhibitors of the HATPCAF with a 2-thioxo-4-thiazolidinone (rhodanine) scaffold attached to a long chain carboxylic acid. Their binding mode was studied by means of docking and molecular dynamics simulations. Structure–activity studies were performed by organic synthesis and in vitro testing in an antibody based biochemical assay showing similar inhibition on the HATs PCAF, Gcn5, CBP and p300 in vitro. In contrast, a pyridoisothiazolone reference inhibitor is more potent on CBP and to some extent on PCAF but less potent on Gcn5. Structural elements were identified that provide the basis for further optimization of the new inhibitors.
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