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

描述(由申请人提供)：我们建议研究表观遗传学在神经元功能和自闭症中的作用。我们的目标是通过关注与自闭症和其他神经功能方面有关但从未在神经系统背景下进行研究的表观遗传调节来提高我们对大脑染色质调节的理解。自闭症谱系障碍(ASD)是一种神经发育综合征，其特征是社交、沟通和行为方面的障碍，大约每100名儿童中就有1人受到影响。尽管ASD的发病率很高，但导致神经元功能障碍的机制尚不清楚。有趣的是，该领域的最新进展表明，自闭症和表观遗传调控之间存在联系。这项提案中描述的多条证据表明，ASD中存在表观遗传调节因子和染色质相关蛋白Brd4。BRD4招募染色质调节酶来靶向启动子来调节转录，但在有丝分裂后神经元中没有已知的功能。然而，Brd4与几种神经疾病之间的联系以及我们在本提案中描述的初步数据强烈表明，它对神经元功能至关重要。我们将研究Brd4在大脑中的调节和功能，包括正常神经元和公认的自闭症模型。我们假设Brd4调节神经元功能的重要方面，如突触强度，调节不当导致转录模式异常，与自闭症FXS模型中观察到的突触异常有关。我们试图在两个特定的目标上检验这一工作假说：1)研究Brd4在神经元中的调节；2)研究Brd4在神经元功能和功能障碍中的作用。阻止BRD4功能的小分子抑制剂的最新发展，并用于人类临床环境，使这一系列研究特别引人注目和及时。在目标1中，我们将研究Brd4表达的调节和Brd4-染色质结合的调节，包括这两者如何受到神经元活动的影响。在目标2中，我们将研究Brd4在调节突触强度变化中的作用，以及它在调节神经元中的转录和染色质景观中的作用。最后，我们将研究Brd4如何影响行为，并将确定抑制Brd4是否可以缓解在ASD小鼠模型中观察到的缺陷。最终，这一建议有可能极大地扩展我们目前对影响正常神经元功能的表观遗传学机制的理解，并提供对ASD的临床相关见解。通过这项工作，我们的目标是促进我们对染色质介导的神经元功能和行为的理解取得重大进展，因为它与人类精神疾病有关。

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.