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Competitive interplay of neuronal transcription factors via DNA methylation

神经元转录因子通过 DNA 甲基化的竞争性相互作用

基本信息

批准号：
9894858
负责人：
Junji Iwahara
金额：
$ 19.36万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894858
关键词：
Binding Biochemical Biophysics Brain Brain Diseases CREB1 gene Calorimetry Cell Nucleus CpG Islands CpG dinucleotide Cyclic AMP Cyclic AMP-Responsive DNA-Binding Protein DNA DNA Methylation Drug Addiction Elements Epigenetic Process Fluorescence Spectroscopy Functional disorder Future Gene Activation Gene Expression Regulation Genes Genetic Predisposition to Disease Genomic DNA Goals Human Human Genome In Vitro Investigation Knowledge Learning Methyl-CpG-Binding Protein 2 Methylation Molecular Mus Mutation NMR Spectroscopy Neurons Pharmacology Phosphorylation Play Proteins Proteomics Research Research Project Grants Rett Syndrome Role Testing Therapeutic Titrations Transactivation Transcription Coactivator Transcription Repressor Transcriptional Activation Transcriptional Activation Domain Transcriptional Regulation autism spectrum disorder biophysical properties biophysical techniques demethylation epigenetic regulation gene repression genetic corepressor insight long term memory novel prevent promoter protein protein interaction screening therapeutic development transcription factor

项目摘要

Abstract In the brain, the transcription factors MeCP2 and CREB play crucial roles in activity-dependent gene regulation for long-term memory formation and learning. Dysfunction of these proteins is associated with brain disorders such as Rett syndrome and drug addiction. MeCP2 was originally identified as a transcriptional repressor that specifically recognizes methylated CpG dinucleotides in DNA. More recently, despite the lack of any known transcriptional activation domain, it was found that neuronal MeCP2 activates more than 2,000 genes under the control of CpG island promoters where DNA methylation is rare. The overall goal of this R21 project is to elucidate the mechanisms by which MeCP2 acts as a transcriptional activator. The central hypothesis tested in this project is that MeCP2 activates many genes by novel dual mechanisms through the direct interaction with CREB and through indirect interplay that prevents CREB1 from being sequestered in nonfunctional decoys. This research project will pursue the following specific aims: 1) characterize the direct interaction between CREB and MeCP2 in vitro and 2) unravel the indirect interplay between these proteins via DNA methylation. The research team will use biophysical and biochemical approaches to examine the dual mechanisms. New knowledge about transactivation by MeCP2 will provide insight into epigenetic regulation in the brain and deepen our understanding of brain disorders. For example, our biophysical characterizations of the CREB-MeCP2 interaction will provide new perspectives for interpreting Rett syndrome mutations of MeCP2. The approaches established through this project would potentially facilitate pharmacological screening of compounds that inhibit the CREB-MeCP2 interaction for drug addiction therapeutics in the future.

摘要在脑中，转录因子MeCP 2和CREB在活动依赖性基因中起关键作用，调节长期记忆的形成和学习。这些蛋白质的功能障碍与诸如雷特综合征和药物成瘾等脑部疾病。MeCP 2最初被确定为特异性识别DNA中甲基化CpG二核苷酸的转录抑制因子。最近，尽管缺乏任何已知的转录激活结构域，但发现神经元MeCP 2激活超过2，000个基因受CpG岛启动子控制，其中DNA甲基化很少见。的这个R21项目的总体目标是阐明MeCP 2作为转录因子的机制，活化剂。在这个项目中测试的中心假设是MeCP 2通过新的双重作用激活许多基因。通过与CREB的直接相互作用和通过阻止CREB 1的间接相互作用，被困在没有功能的诱饵里本研究项目将开展以下具体工作：目的：1）表征CREB和MeCP 2之间的体外直接相互作用，2）阐明CREB和MeCP 2之间的间接相互作用。这些蛋白质之间通过DNA甲基化相互作用。研究小组将使用生物物理和生化方法来检查双重机制。关于MeCP 2反式激活的新知识将提供对大脑表观遗传调控的深入了解，并加深我们对大脑疾病的理解。例如，我们对CREB-MeCP 2相互作用的生物物理表征将提供新的解释MeCP 2的Rett综合征突变的观点。通过这种方式建立的方法该项目将有可能促进抑制CREB-MeCP 2的化合物的药理学筛选未来药物成瘾治疗的相互作用。