title: Autism-like syndrome is induced by pharmacological suppression of BET proteins in young mice.
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.
authors.affiliation: Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Josefa M
authors.initials: JM
authors.lastname: Sullivan
authors.affiliation: Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Ana
authors.initials: A
authors.lastname: Badimon
authors.affiliation: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065.
authors.forename: Uwe
authors.initials: U
authors.lastname: Schaefer
authors.affiliation: Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Pinar
authors.initials: P
authors.lastname: Ayata
authors.affiliation: Epinova DPU, Quantitative Pharmacology, and Platform Technology and Science, Immuno-Inflammation Therapy Area, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, England, UK Epinova DPU, Quantitative Pharmacology, and Platform Technology and Science, Immuno-Inflammation Therapy Area, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, England, UK.
authors.forename: James
authors.initials: J
authors.lastname: Gray
authors.affiliation: Epinova DPU, Quantitative Pharmacology, and Platform Technology and Science, Immuno-Inflammation Therapy Area, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, England, UK.
authors.forename: Chun-wa
authors.initials: CW
authors.lastname: Chung
authors.affiliation: Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Melanie
authors.initials: M
authors.lastname: von Schimmelmann
authors.affiliation: Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Epinova DPU, Quantitative Pharmacology, and Platform Technology and Science, Immuno-Inflammation Therapy Area, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, England, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Garton
authors.affiliation: Epinova DPU, Quantitative Pharmacology, and Platform Technology and Science, Immuno-Inflammation Therapy Area, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, England, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Smithers
authors.affiliation: Epinova DPU, Quantitative Pharmacology, and Platform Technology and Science, Immuno-Inflammation Therapy Area, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, England, UK.
authors.forename: Huw
authors.initials: H
authors.lastname: Lewis
authors.affiliation: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tarakhovsky
authors.affiliation: Epinova DPU, Quantitative Pharmacology, and Platform Technology and Science, Immuno-Inflammation Therapy Area, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, England, UK.
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.affiliation: Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 Department of Neuroscience and Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 anne.schaefer@mssm.edu.
authors.forename: Anne
authors.initials: A
authors.lastname: Schaefer
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000209:etiology* / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D044127:Epigenesis, Genetic; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C486765:Dner protein, mouse; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface