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Synthetic antagonist of a histone reader reveals and targets genes essential for inflammation

ABSTRACT: Post-translational modifications of histones determines cell lineage- or signal-specific gene expression. Depending on the type and combination of modifications, histones bind to functionally distinct effector proteins ('readers') that control gene activation or silencing. The current pharmacological modulation of the epigenome aims to control gene expression by regulation of the enzymes that catalyze post-translational histone modifications. Here we present a novel pharmacological approach that targets gene expression by interfering with the function of histone ?readers?. We describe the impact of a synthetic compound that selectively occupies the acetylated histone-binding pocket of the Bromodomain and Extra Terminal domain (BET) family of proteins and prevents their interaction with acetylated histones. The bromodomain blocking compound suppresses the expression of a specific subset of key inflammatory genes in activated macrophages and confers protection against LPS-induced septic shock in vivo. Our findings suggest that small molecules specifically targeting histone 'readers' can serve as a new generation of drugs to treat immune diseases. Microarray, ChIP-qPCR and ChIP-seq examination of control, 1H LPS stimulated bone-marrow-derived macrophages in the presence/absence of acetylated histone mimic in mouse.

ORGANISM(S): Mus musculus  

SUBMITTER: Scott Dewell   Uwe Schaefer 

PROVIDER: E-GEOD-21910 | ArrayExpress | 2010-11-10



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Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression. Recognition of post-tran  ...[more]

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