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Regulation of Alternative Splicing in the Brain by a Large Assembly of Splicing Regulators

大量剪接调节器对大脑中选择性剪接的调节

基本信息

批准号：
10641757
负责人：
Parham Peyda
金额：
$ 4.23万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641757
关键词：
Affect Alternative Splicing Binding Binding Proteins Binding Sites Biochemical Brain Cells Co-Immunoprecipitations Code Complex Dependence Disease Epilepsy Event Exons Family Genes Heterogeneous-Nuclear Ribonucleoprotein Group M Heterogeneous-Nuclear Ribonucleoproteins Hippocampus Immunoprecipitation Individual Informatin Introns Knockout Mice Maps Mass Spectrum Analysis Mental disorders Methods Mus Mutate Mutation Neurons Nuclear RNA Pathway interactions Play Process Protein Family Protein Splicing Proteins RNA RNA Binding RNA Splicing RNA-Binding Proteins RNA-Protein Interaction Regulation Regulator Genes Role Sedimentation process Shapes Site Transcript Wild Type Mouse autism spectrum disorder cofactor combinatorial crosslink experimental study genetic regulatory protein genome-wide analysis hnRNP-H insight knock-down nervous system disorder neuron component neuron development novel nuclease protein complex recruit transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY/ABSTRACT Alternative splicing is a key process in shaping the functional complexity of the brain. Accordingly, many neurologic and psychiatric disorders are caused by mutations in RNA binding proteins or their targets in alternative splicing. The Rbfox family of RNA Binding proteins regulate alternative splicing during neuronal development and their mutations have been implicated in autism spectrum disorder and various familial epileptic disorders. To understand the role of Rbfox in these diseases, many studies have focused on how individual Rbfox proteins bind to their targets and regulate their splicing. However, Rbfox proteins are also known to interact with cofactors that influence their function. We previously found that nuclear Rbfox proteins in the mouse brain are almost exclusively bound to a large assembly of splicing regulators (LASR). However, it remains unknown what the full subunits of the neuronal LASR complex are and how they interact with Rbfox to regulate alternative splicing in neurons. In this proposal, I will define the neuronal components of LASR, determine the transcriptome-wide targets of the LASR/Rbfox complex and its subunits in the mouse brain, and analyze how components of LASR affect Rbfox’s splicing regulatory activity in neurons. These studies will elucidate how combinatorial interactions between RNA binding proteins in a novel splicing regulatory protein complex shape the gene regulatory circuit of the brain and will further our understanding of the function of the Rbfox proteins which have been implicated in epilepsy and autism spectrum disorder.

项目概要/摘要选择性剪接是塑造大脑功能复杂性的关键过程。据此，许多神经系统和精神疾病是由 RNA 结合蛋白或其靶点的突变引起的选择性拼接。 RNA 结合蛋白的 Rbfox 家族在神经元过程中调节选择性剪接发育及其突变与自闭症谱系障碍和各种家族遗传有关癫痫疾病。为了了解 Rbfox 在这些疾病中的作用，许多研究都集中于如何单个 Rbfox 蛋白与其靶标结合并调节其剪接。然而，Rbfox 蛋白也已知与影响其功能的辅助因子相互作用。我们之前发现核中的 Rbfox 蛋白小鼠大脑几乎完全与大量剪接调节器（LASR）结合。然而，它目前仍不清楚神经元 LASR 复合体的完整亚基是什么以及它们如何与 Rbfox 相互作用以实现调节神经元中的选择性剪接。在本提案中，我将定义 LASR 的神经元组成部分，确定小鼠大脑中 LASR/Rbfox 复合物及其亚基的转录组范围目标，以及分析 LASR 的成分如何影响 Rbfox 在神经元中的剪接调节活性。这些研究将阐明新型剪接调节蛋白中 RNA 结合蛋白之间的组合相互作用复杂的大脑基因调节回路的形状，将进一步我们对大脑功能的理解 Rbfox 蛋白与癫痫和自闭症谱系障碍有关。