Autism-like syndrome is induced in mice by pharmacological suppression of BET proteins

Studies investigating the causes of autism spectrum disorder (ASD) point to genetic as well as epigenetic mechanisms of the disease. Identification of epigenetic processes that contribute to ASD development and progression is of major importance and may lead to the development of novel therapeutic strategies. Here we identify the bromodomain and extra-terminal domain containing transcriptional regulators (BETs) as epigenetic drivers of an ASD-like disorder in mice. We found that the pharmacological suppression of the BET proteins by a novel, highly selective and brain-permeable inhibitor, I-BET858, leads to selective suppression of neuronal gene expression followed by the development of an autism-like syndrome in mice. Many of the I-BET858 affected genes have been linked to ASD in humans thus suggesting the key role of the BET-controlled gene network in ASD. Our studies also suggest that environmental factors controlling BET proteins or their target genes may contribute to the epigenetic mechanism of ASD.

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Sullivan JM, Badimon A, Schaefer U, Ayata P, Gray J, Chung CW, von Schimmelmann M, Zhang F, Garton N, Smithers N, Lewis H, Tarakhovsky A, Prinjha RK, Schaefer A