Chromatin modifications that regulate transcription at the neuromuscular synapse

描述(申请人提供)：拟议的研究重点是一种信号通路，它有助于指导神经肌肉突触的形成和组织，并解决这一途径如何通过诱导染色质特定区域的修饰来调节转录。乙酰胆碱受体(AChRs)在肌肉突触后区域的定位被认为是部分由转录机制介导的，因为编码AChR亚单位的基因在突触肌纤维核中选择性地转录，这被认为是理解突触形成的基础。神经调节蛋白-1(NRG-1)是一种潜在的细胞外配体，可刺激突触特异性转录。NRG-1诱导的AChR转录需要两个转录调控元件，一个结合GA结合蛋白(GABP)，另一个结合早期生长反应-1(Egr-1)，但GABP和Egr-1诱导转录响应NRG-1的机制尚不清楚。转录激活可以通过对染色质的局部修饰来介导，执行这些修饰的蛋白质通常通过与DNA结合蛋白形成复合体而被招募到染色质的特定区域。NRG-1诱导染色质的修饰，通常与AChR基因所在的转录激活有关；增加了NRG-1部分通过修改染色质的特定区域激活转录的可能性。在拟议的研究中，实验将分析NRG-1诱导的染色质修饰以及GABP、Egr-1及其相互作用蛋白在促进这些修饰中的作用。除了提供有关神经肌肉突触发育的信息外，这项研究还可能对结构相似的中枢神经系统(CNS)中的突触有深入的了解。中枢神经系统中突触及其连接性的变化调节学习和记忆，类似的机制可能控制它们的形成和组织。由于在许多神经退行性疾病中，中枢神经系统中的突触会出现缺陷，了解这些机制可能有助于恢复正常的突触。

DESCRIPTION (provided by applicant): The proposed research focuses on a signaling pathway that helps to direct the formation and organization of neuromuscular synapses and addresses how this pathway might regulate transcription by inducing modifications to certain regions of chromatin. Localization of acetylcholine receptors (AChRs) to the postsynaptic region of muscle, which is studied as a basis for understanding how synapses form, is believed to be mediated in part by transcriptional mechanisms because the genes encoding AChR subunits are transcribed selectively in synaptic myofiber nuclei. Neuregulin-1 (NRG-1) is a potential extracellular ligand that stimulates synapse-specific transcription. NRG-1-induced AChR transcription requires two transcriptional regulatory elements, one that binds GA-binding protein (GABP) and another that binds early growth respone-1 (Egr-1), but the mechanisms by which GABP and Egr-1 induce transcription in response to NRG-1 are not known. Transcriptional activation can be mediated by local modifications to chromatin, and proteins that perform these modifications typically are recruited to specific regions of chromatin by forming complexes with DNA-binding proteins. NRG-1 induces a modification to chromatin typically associated with transcriptional activation where an AChR gene is located; raising the possibility that NRG-1 activates transcription in part by modifying specific regions of chromatin. Experiments in the proposed research will analyze NRG-1-induced modifications to chromatin and the roles of GABP, Egr-1, and their interacting proteins in facilitating these modifications. In addition to providing information on neuromuscular synapse development, this research may also yield insight into synapses in the central nervous system (CNS), which are structurally similar. Changes to synapses and their connectivity in the CNS mediate learning and memory, and similar mechanisms may control their formation and organization. Because synapses in the CNS become defective in many neurodegenerative diseases, understanding these mechanisms might be useful for restoring proper synapses.