Transcription mechanism of Myrf for central nervous system myelination

Myrf对中枢神经系统髓鞘形成的转录机制

• 批准号: 9294191
• 负责人: YUNGKI PARK
• 金额: $ 38.55万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294191
• 关键词: Adult; Applications Grants; Binding; Biogenesis; Bioinformatics; Biological Assay; Cell Line; Cell Nucleus; ChIP-seq; Cleaved cell; Collaborations; Computer Analysis; Cues; DNA; Data; Development; Endoplasmic Reticulum; Genetic Transcription; Genetic study; Homo; Immunofluorescence Immunologic; Immunoprecipitation; Impairment; In Vitro; Investigation; Laboratories; Learning; Life; Link; Luciferases; Maintenance; Mass Spectrum Analysis; Mediating; Membrane; Membrane Proteins; Modeling; Molecular; Molecular Chaperones; Mus; Mutagenesis; Myelin; N-terminal; Names; Nature; Neuraxis; Oligodendroglia; Phenotype; Proteolysis; Publishing; Regulation; Role; Small Interfering RNA; Specificity; Stimulus; Sum; Tertiary Protein Structure; Thick; Transcriptional Regulation; Western Blotting; Work; chromatin protein; combinatorial; experimental analysis; experimental study; myelination; nervous system disorder; neuropsychiatric disorder; notch protein; novel; protein complex; public health relevance; transcription factor

 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.

 描述（由申请人提供）：少突胶质细胞（OL）对中枢神经系统（CNS）的髓鞘化对于 CNS 的发育和功能至关重要，因为 OL 分化为形成髓鞘的成熟表型。 OLs 受到严格的调控，其失调会导致神经系统疾病，并与神经精神疾病有关。遗传学研究表明，Myrf 是发育的关键转录因子。最近的研究还表明，Myrf 对于调节髓磷脂厚度及其可塑性至关重要，而髓磷脂是成人阶段学习的基础，但人们对 Myrf 的作用仍知之甚少。利用生物信息学和实验方法，我们最近取得了突破性的观察结果：Myrf 是一种膜结合转录因子，并且 Myrf 可能作为一种转录因子。膜结合转录因子作为膜蛋白产生，在相关刺激下，经过蛋白水解激活，从膜上释放转录因子结构域，Notch 是最著名的例子，我们的发现从根本上改变了 Myrf 的范例。 ，基于这一发现，我将阐明 Myrf 如何被蛋白水解激活。 Myrf 的蛋白水解激活从膜中释放其 N 末端片段， Aim II 将决定 Myrf 的 N 末端片段如何作为同源三聚体与 DNA 相互作用以进行转录。 Myrf 的转录活性将阐明哪些转录因子与 yrf 相互作用以协调 OL 的分化。总之，本研究将阐明 Myrf 对于 OL 分化和 CNS 的转录机制。髓鞘形成。