Identifying oligodendrocyte enhancers that govern the expression of Olig1/2

项目摘要 少突胶质细胞(OLs)对中枢神经系统(CNS)的髓鞘形成是发育所必需的 和中枢神经系统的功能。遗传学研究表明，寡核苷酸1/2，碱性螺旋-环-螺旋转录因子， 都是OL系细胞的主要调节者，在发育和再生过程中发挥着不可或缺的作用 中枢神经系统髓鞘。围绕寡核苷酸1/2的一个基本但尚未解决的问题是，谁来调控它们的表达。 显然，对于正常的OL发育，它们必须在OL的正确时间以正确的水平表达 血统细胞。是什么监管机制保证了这一点？迈向这一重大挑战的第一个关键步骤是 确定控制其表达的OL增强剂。从历史上看，为基因寻找增强子一直很困难。 为了在这一根本问题上取得突破，我们开发了一种新的方法，利用 关于我们对基因组组织和增强子的理解的最新进展。我们已经展示了它的 通过将其应用于Myrf来增强力量，发现了两个OL增强子，其中包括一个新的，共同调节Myrf 表达，以及时分化的OL。这笔赠款将利用这一新的强大的方法来 找出控制寡核苷酸2(目标I)和寡核苷酸1(目标II)表达的OL增强子。 。

Project Summary Myelination of the central nervous system (CNS) by oligodendrocytes (OLs) is essential for the development and function of the CNS. Genetic studies have shown that Olig1/2, basic helix-loop-helix transcription factors, are master regulators of OL lineage cells, playing an indispensable role in the development and regeneration of CNS myelin. A fundamental yet unresolved issue surrounding Olig1/2 is who regulates their expression. Apparently, for proper OL development, they have to be expressed at the right level at the right moment in OL lineage cells. What regulatory mechanism ensures it? The first critical step toward this grand challenge is to identify OL enhancers that govern their expression. Historically, finding enhancers for a gene has been difficult. To make a breakthrough for this fundamental issue, we have developed a novel method that takes advantage of recent advances in our understanding of genome organization and enhancers. We have demonstrated its power by applying it to Myrf, uncovering two OL enhancers, including one novel one, that jointly regulate Myrf expression for timely differentiation of OLs. This grant will capitalize on this new powerful method in order to identify OL enhancers that govern the expression of Olig2 (Aim I) and Olig1 (Aim II). .