Autism Spectrum Disorder (ASD) is a group of complex neurodevelopmental disorders that affect 1 in 68 children in the United States. The severity and symptoms of ASD cases vary greatly, but the disorder is characterized by social impairment and repetitive behaviors. ASD represents a major health burden as there is currently no cure and treatments rely on intensive behavioral interventions which have varying efficacy. There is no known single cause for ASD, but it is clear that there are strong genetic and environmental components to the development of the disorder. Recent studies implicated the regulation of gene transcription as a crucial process in the etiology of ASD. Our previous findings identify the bromodomain and extraterminal domain containing (BET) proteins, as epigenetic regulators of neuronal and synaptic genes involved in ASD-like behaviors in mice. We found that the pharmacological suppression of BET proteins in the brain of young mice, leads to selective suppression of neuronal gene expression followed by the development of an autism-like syndrome. Many of the BET-dependent genes have been identified as risk factors for ASD in humans, suggesting a key role of the BET-controlled gene network in the disorder. In this proposal, I will address the biochemical and molecular mechanisms by which BETs, and specifically Brd4, regulate the transcription of neuronal genes implicated in ASD and the development of abnormal social behaviors. These studies will elucidate how impaired gene transcription can lead to abnormal brain development and thus inform our understanding of ASD etiology.
Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disorders and represents a substantial economic and social burden due to insufficient therapeutic strategies and an incomplete understanding of its causes. Recent genetic studies implicated transcriptional regulators as a key component underlying ASD pathology. This proposal will investigate the role of an epigenetic regulator, Brd4, in controlling neuronal gene expression and the generation of social behaviors in developing rodents, potentially clarifying how defective transcription can lead to abnormal brain development.
| Ayata, Pinar; Badimon, Ana; Strasburger, Hayley J et al. (2018) Epigenetic regulation of brain region-specific microglia clearance activity. Nat Neurosci 21:1049-1060 |
