The role of the epigenetic regulator Brd4 in neuronal function and autism

DESCRIPTION (provided by applicant): We propose to examine the role of epigenetics in neuronal function and autism. Our aim is to improve our understanding of chromatin regulation in brain by focusing on epigenetic regulations that are implicated in autism and other aspects of neurological function but have never been investigated in the context of the nervous system. Autism spectrum disorders (ASD) are neurodevelopmental syndromes characterized by impairments in socialization, communication and behavior that affect approximately 1 in 100 children. Despite the high prevalence of ASD, the mechanisms resulting in neuronal dysfunction are poorly understood. Interestingly, recent advances in the field suggest there is a link between autism and epigenetic regulation. Multiple lines of evidence described in this proposal implicate the epigenetic regulator and chromatin- associated protein Brd4 in ASD. Brd4 recruits chromatin-regulating enzymes to target promoters to regulate transcription but has no known function in post-mitotic neurons. However, links between Brd4 and several neurological disorders as well as the preliminary data we describe in this proposal strongly suggest it is critical to neuronal function. We will examine the regulation and function of Brd4 in brain, both i normal neurons and in a well-established model of autism. We hypothesize that Brd4 regulates important aspects of neuronal function such as synaptic strength and that misregulation leads to aberrant patterns of transcription associated with the synaptic abnormalities observed in the FXS model of autism. We seek to test this working hypothesis in two Specific Aims: 1) Investigate the regulation of Brd4 in neurons and 2) Investigate the role of Brd4 in neuronal function and dysfunction. The recent development of small molecule inhibitors that prevent BRD4 function and are used in human clinical settings make this line of research particularly compelling and timely. In Aim 1 we will examine both regulation of the expression of Brd4 and regulation of Brd4-chromatin associations, including how both of these are affected by neuronal activity. In Aim 2, we will examine the role of Brd4 in mediating changes in synaptic strength as well as its role in regulating transcription and the chromatin landscape in neurons. Finally, we will examine how Brd4 affects behavior and will determine if inhibition of Brd4 can alleviate deficits observed in a mouse model of ASD. Ultimately, this proposal has the potential to greatly expand our current understanding of the epigenetic mechanisms influencing normal neuronal function and provide clinically relevant insights into ASDs. Through this work, we aim to promote significant advances in our understanding of chromatin-mediated neuronal function and behavior, as it relates to human psychiatric disease.

DESCRIPTION (provided by applicant): We propose to examine the role of epigenetics in neuronal function and autism. Our aim is to improve our understanding of chromatin regulation in brain by focusing on epigenetic regulations that are implicated in autism and other aspects of neurological function but have never been investigated in the context of the nervous system. Autism spectrum disorders (ASD) are neurodevelopmental syndromes characterized by impairments in socialization, communication and behavior that affect approximately 1 in 100 children. Despite the high prevalence of ASD, the mechanisms resulting in neuronal dysfunction are poorly understood. Interestingly, recent advances in the field suggest there is a link between autism and epigenetic regulation. Multiple lines of evidence described in this proposal implicate the epigenetic regulator and chromatin- associated protein Brd4 in ASD. Brd4 recruits chromatin-regulating enzymes to target promoters to regulate transcription but has no known function in post-mitotic neurons. However, links between Brd4 and several neurological disorders as well as the preliminary data we describe in this proposal strongly suggest it is critical to neuronal function. We will examine the regulation and function of Brd4 in brain, both i normal neurons and in a well-established model of autism. We hypothesize that Brd4 regulates important aspects of neuronal function such as synaptic strength and that misregulation leads to aberrant patterns of transcription associated with the synaptic abnormalities observed in the FXS model of autism. We seek to test this working hypothesis in two Specific Aims: 1) Investigate the regulation of Brd4 in neurons and 2) Investigate the role of Brd4 in neuronal function and dysfunction. The recent development of small molecule inhibitors that prevent BRD4 function and are used in human clinical settings make this line of research particularly compelling and timely. In Aim 1 we will examine both regulation of the expression of Brd4 and regulation of Brd4-chromatin associations, including how both of these are affected by neuronal activity. In Aim 2, we will examine the role of Brd4 in mediating changes in synaptic strength as well as its role in regulating transcription and the chromatin landscape in neurons. Finally, we will examine how Brd4 affects behavior and will determine if inhibition of Brd4 can alleviate deficits observed in a mouse model of ASD. Ultimately, this proposal has the potential to greatly expand our current understanding of the epigenetic mechanisms influencing normal neuronal function and provide clinically relevant insights into ASDs. Through this work, we aim to promote significant advances in our understanding of chromatin-mediated neuronal function and behavior, as it relates to human psychiatric disease.