Mechanisms of SWI/SNF complex assembly and function

项目摘要 染色质重塑复合物在调节基因表达、分化和免疫应答中起关键作用。 发展SWI/SNF染色质重塑复合物在约25%的人类肿瘤中发生突变。的 SWI/SNF内的12-15个位置由~30个独特亚基填充。这些组合体 基因可以产生1000-2000种生物化学上不同的复合物。虽然经常作为一个单一的复杂的研究，这些 SWI/SNF的生物化学上不同的形式在基因调控中具有不同的功能。 调节SWI/SNF功能的机制，因此在SWI/SNF突变肿瘤中被破坏， 对开发新疗法至关重要。 我们认为，SWI/SNF的翻译后修饰以及SWI/SNF与RNA的相互作用可能与SWI/SNF的功能有关。 调节复合物的功能。了解这些机制如何影响不同的SWI/SNF 复合物的定义是我实验室的重点。我们将在本项目中解决的关键问题是1。做 不同的SWI/SNF复合物具有不同的功能？2.）的情况。是什么在生物化学上调节着 不同的复合体3.）第三章如何调节复合物的组成和靶向的变化？我们实验室 结合计算，分子和生物化学分析来回答这些问题，并深入研究 深入了解SWI/SNF活性的机制。在接下来的五年里，我们将研究 联合收割机调节SWI/SNF的组成和功能，并确定不同的功能结果 由不同的SWI/SNF复合物介导。鉴于SWI/SNF在发育和疾病中的关键作用， 了解复合体如何调节以调节不同的结果对于开发新的 针对癌症和其他疾病的方法。

Project Summary Chromatin remodeling complexes play a critical role in regulating gene expression, differentiation, and development. The SWI/SNF chromatin remodeling complex is mutated in ~25% of all human tumors. The 12-15 positions within SWI/SNF are filled from ~30 unique subunits. The combinatorial assembly of these genes can yield 1000-2000 biochemically distinct complexes . While often studied as a single complex, these biochemically distinct forms of SWI/SNF have different functions in gene regulation.Understanding the mechanisms that regulate SWI/SNF function, and that are therefore disrupted in SWI/SNF mutant tumors, is of critical importance for developing new therapies. We propose that post-translational modifications of SWI/SNF and interactions between SWI/SNF and RNA modulate function of the complex. Understanding how these mechanisms contribute to how different SWI/SNF complexes are defined is the focus of my lab. The key questions we will address in this project are 1.) Do variant SWI/SNF complexes have different functions? 2.) What regulates different activities of biochemically distinct complexes? 3.) How are changes to the composition and the targeting of complexes regulated? Our lab combines computational, molecular, and biochemical analyses to answer these questions and develop deeper insight into the mechanisms of SWI/SNF activity. Over the next five years, we will investigate mechanisms that combine to regulate the composition and function of SWI/SNF and determine how different functional outcomes are mediated by distinct SWI/SNF complexes. Given the critical role of SWI/SNF in development and disease, understanding how the complex is regulated to mediate different outcomes is critical for developing new approaches to targeting cancer and other diseases.