Epigenetic Regulation of the IL-13-induced Human Eotaxin-3 Gene by CREB-binding Protein-mediated Histone 3 Acetylation

Abstract

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.

DNA methyl transferase I acts as a negative regulator of allergic skin inflammation

“…Expression of IL-13, a Th2 cytokine, is subjected to epigenetic regulation (Lim et al, 2011). TNF-␣ induces expression of adhesion molecules and vascular permeability (Lee et al, 2012).…”

Genetic and Epigenetic Underpinnings of Eosinophilic Esophagitis

“…The mapping of two STAT6 binding sites roughly established the promoter proximal regions required for IL-13-induced transcriptional activation of CCL26 (30). Further analysis demonstrated a requirement for two co-activators, activating transcription factor 2 (ATF2) and the histone acetyltransferase cAMP-responsive element (CRE)-binding protein (CBP) (50). Chromatin immunoprecipitation (ChIP) assays indicated that STAT6, CBP, ATF2, and acetylated histone 3 bound within the same region of the CCL26 promoter in esophageal epithelial cells following IL-13 treatment (50).…”

“…Further analysis demonstrated a requirement for two co-activators, activating transcription factor 2 (ATF2) and the histone acetyltransferase cAMP-responsive element (CRE)-binding protein (CBP) (50). Chromatin immunoprecipitation (ChIP) assays indicated that STAT6, CBP, ATF2, and acetylated histone 3 bound within the same region of the CCL26 promoter in esophageal epithelial cells following IL-13 treatment (50). Thus, IL-13 induces the formation of a multi-protein complex on the CCL26 promoter that includes CBP, leading to increases in acetylated histone 3 and opening of the CCL26 promoter for additional transcriptional machinery.…”

“… 1 EoE was a comorbidity in one of three SAM syndrome patients 2 High prevalence of EoE and other EGlDs (n = 6) in 58 LDS patients 3 Significant enrichment of EGID in PHTS (odds ratio = 272; confidence interval 89-831, P < 10 −4 ) Data from Refs 3,4,14,16,17,19,19,20,22,23,27,37,40,45,46,50,51,54,56-59,62. …”

High Expression of H3K9me3 Is a Strong Predictor of Poor Survival in Patients With Salivary Adenoid Cystic Carcinoma

“…However, histone modifications appear to play important roles in organizing the nuclear architecture, with consequent effects on the regulation of gene transcription. 4,12 Histone H3 lysine 9 trimethylation (H3K9me3) is a histone modification that occurs in the N-terminal of lysine residues. It has been correlated with tumor suppressor gene silencing in colorectal cancer, 13 hepatocellular cancer, 14 and breast cancer.…”