Transcription mechanism of Myrf for central nervous system myelination

 描述(申请人提供)：少突胶质细胞对中枢神经系统(CNS)的髓鞘形成是中枢神经系统发育和功能所必需的。随着OL分化为形成髓鞘的成熟表型，髓鞘在中枢神经系统发育。OL的分化受到严格的调控，其调节失调会导致神经紊乱，并与神经精神疾病有关。遗传学研究表明，Myrf是中枢神经系统髓鞘发育和终生维持的关键转录因子。最近的研究还表明，Myrf对于微调髓鞘厚度及其可塑性至关重要，这是成年阶段学习的基础。尽管发挥了这些关键作用，但对Myrf如何调控转录仍然知之甚少，这严重阻碍了这一领域的进展。利用生物信息学和实验方法，我们最近取得了突破性的发现：Myrf是一个膜结合的转录因子，并且Myrf可能是一个同源三聚体转录因子。膜结合转录因子是以膜蛋白的形式产生的，在相关刺激下，膜蛋白被激活，从而从膜上释放转录因子结构域，Notch就是最著名的例子。我们的发现从根本上改变了Myrf的范式，为理解其作用机制提供了一个强大的框架。在这一发现的基础上，AIM I将阐明Myrf是如何被蛋白质分解激活的。Myrf的蛋白水解性激活从膜上释放其N-末端片段，使其能够移位到细胞核中进行转录调节。目的II将确定Myrf的N-末端片段如何作为转录的同源三聚体与DNA相互作用。我们的计算和实验分析表明，与其他转录因子的功能协作对Myrf的转录活性至关重要。目的III将阐明哪些转录因子与YRF相互作用以协调OL的分化。综上所述，本研究将阐明Myrf在OL分化和中枢神经系统髓鞘形成中的转录机制。

 DESCRIPTION (provided by applicant): Myelination of the central nervous system (CNS) by oligodendrocytes (OLs) is essential for the development and function of the CNS. Myelin develops in the CNS as OLs differentiate into the myelin-forming mature phenotype. The differentiation of OLs is under tight regulation, and its dysregulation causes neurological disorders and has been linked to neuropsychiatric diseases. Genetic studies have shown that Myrf is a key transcription factor for the development and life-long maintenance of myelin in the CNS. Recent studies have also demonstrated that Myrf is critical to the fine-tuning of myelin thickness and its plasticity that underlies learning in the adult stage. Despite these crucial role, it remains poorly understood how Myrf regulates transcription, and this significantly impedes the progress in this field. Using bioinformatics and experimental approaches, we recently made the breakthrough observations that Myrf is a membrane-bound transcription factor, and that Myrf may function as a homo-trimeric transcription factor. Membrane-bound transcription factors are generated as membrane proteins that, upon relevant stimuli, undergo proteolytic activation to release transcription factor domains from the membrane, with Notch being the most famous example. Our discovery fundamentally changes the paradigm for Myrf, providing a powerful framework to understand its functional mechanism. Building upon this discovery, Aim I will elucidate how Myrf is activated by proteolysis. The proteolytic activation of Myrf releases its N-terminal fragment from the membrane, allowing it to translocate into the nucleus for transcriptional regulation. Aim II will determine how the N-terminal fragment of Myrf interacts with DNA as a homo-trimer for transcription. Our computational and experimental analyses indicate that functional collaboration with other transcription factors is critical to the transcriptional activity of Myrf. Aim III will elucidate which transcription factors interact with yrf for coordinated differentiation of OLs. In sum, this study will elucidate the transcription mechanism of Myrf for OL differentiation and CNS myelination.