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

Josefa M. Sullivan, Ana Badimon, Uwe Schaefer, Pinar Ayata, James Gray, Chun Wa Chung, Melanie von Schimmelmann, Fan Zhang, Neil Garton, Nicholas Smithers, Huw Lewis, Alexander Tarakhovsky, Rab K. Prinjha, Anne Schaefer

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

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 extraterminal domain-containing proteins (BETs) as epigenetic regulators of genes involved in ASD-like behaviors in mice. We found that the pharmacological suppression of BET proteins in the brain of young mice, by the novel, highly specific, brain-permeable inhibitor I-BET858 leads to selective suppression of neuronal gene expression followed by the development of an autism-like syndrome. 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 the disorder. Our studies suggest that environmental factors controlling BET proteins or their target genes may contribute to the epigenetic mechanism of ASD.

Original languageEnglish
Pages (from-to)1771-1781
Number of pages11
JournalJournal of Experimental Medicine
Volume212
Issue number11
DOIs
StatePublished - 19 Oct 2015

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