m6A 在 HNRNPG 蛋白定位和 HNRNPG 调节的选择性剪接中的作用-猫眼课题宝

m6A 在 HNRNPG 蛋白定位和 HNRNPG 调节的选择性剪接中的作用

批准号：

9388261

负责人：

Katherine Ismei Zhou

金额：

$4.9万

依托单位：

UNIVERSITY OF CHICAGO

依托单位国家：

美国

项目类别：

财政年份：

2016

资助国家：

美国

项目状态：

已结题

起止时间：

2016-07-08 至 2019-07-07

来源：

https://reporter.nih.gov/project-details/9388261

关键词：

Alternative Splicing Binding Binding Proteins Binding Sites CRISPR/Cas technology Cell Nucleus Cell physiology Cells Clustered Regularly Interspaced Short Palindromic Repeats Complex Cytoplasm Cytoplasmic Granules DNA Repair Data Disease Eukaryota Event Exons G-substrate GTP-Binding Proteins Genes Heterogeneous-Nuclear Ribonucleoprotein Group C Heterogeneous-Nuclear Ribonucleoproteins Homeostasis Individual Introns Investigation Lead Link Localized Disease MALAT1 gene MAPT gene Mediating Messenger RNA Methods Methyltransferase Modeling Modification Motor Neurons Mutation Neuromuscular Diseases Nuclear Nuclear Protein Nucleoplasm Physiological Processes Play Post-Translational Protein Processing Process Proteins RNA RNA Binding RNA Processing RNA Splicing RNA, Messenger, Splicing Reader Recruitment Activity Regulation Reverse Transcription Role Sister Chromatid Site Spermatogenesis Structure Technology Testing Therapeutic Transcript Transcriptional Regulation Translations Untranslated RNA Work cohesion crosslink human disease knock-down nervous system disorder neurodevelopment novel nucleocytoplasmic transport protein biomarkers protein function stem stem cell differentiation

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中文摘要

翻译

摘要 N6-甲基腺苷(M6A)是最常见的信使RNA和长非编码RNA修饰真核生物。通过对RNA加工、输出、翻译和衰变的影响，m6A影响不同的包括干细胞分化、能量动态平衡和精子发生的过程。细胞功能 M6A的识别是通过M6A阅读器蛋白的识别来介导的。异质核糖核蛋白 G(HNRNPG)是一种新的m6A阅读器蛋白，它在神经发育中发挥功能，并调节几个与神经肌肉疾病相关的选择性剪接事件。我们的初步数据表明，m6A会影响 HNRNPG的细胞定位以及M6A和HNRNPG共同调节~1,000的选择性剪接含有M6A的转录本。为了研究m6A是如何调节HNRNPG定位的，我将研究它的功能研究特定的m6A修饰的lncRNA在HNRNPG核保留中的作用，我将确定核- 胞质穿梭在HNRNPG的细胞功能中。调查M6A如何影响HNRNPG调节替代剪接事件，我将使用下拉方法来确定招募到M6A- HNRNPG修改的转录本，我将研究这些剪接因子的敲除如何影响另一种拼接。以m6A阅读器HNRNPG为模型，这些研究将阐明新的机制通过m6A影响蛋白质定位和选择性剪接，这两个关键的细胞过程是在各种人类疾病中被破坏。

英文摘要

Abstract N6-methyladenosine (m6A) is the most common messenger RNA and long noncoding RNA modification in eukaryotes. Through its effects on RNA processing, export, translation, and decay, m6A influences diverse processes including stem cell differentiation, energy homeostasis, and spermatogenesis. The cellular functions of m6A are mediated through its recognition by m6A reader proteins. Heterogeneous nuclear ribonucleoprotein G (HNRNPG) is a novel m6A reader protein that functions in neural development and regulates several alternative splicing events linked to neuromuscular diseases. Our preliminary data indicate that m6A influences the cellular localization of HNRNPG, and that m6A and HNRNPG co-regulate the alternative splicing of ~1,000 m6A-containing transcripts. To investigate how m6A regulates HNRNPG localization, I will examine the function of a specific m6A-modified lncRNA in the nuclear retention of HNRNPG, and I will determine the role of nucleo- cytoplasmic shuttling in the cellular function of HNRNPG. To investigate how m6A impacts HNRNPG-regulated alternative splicing events, I will use a pull-down approach to identify splicing factors that are recruited to m6A- modified transcripts by HNRNPG, and I will examine how knockdown of these splicing factors influences alternative splicing. Using the m6A reader HNRNPG as a model, these studies will elucidate novel mechanisms by which m6A influences protein localization and alternative splicing, two crucial cellular processes that are disrupted in a variety of human diseases.

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