How MeCP2 discriminates epigenetic marks is still a mystery

MeCP2如何区分表观遗传标记仍然是个谜

基本信息

批准号：
10201657
负责人：
Michael D. Brenowitz
金额：
$ 33.4万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201657
关键词：
Binding Binding Proteins Biological Process Brain C-terminal Cell physiology Chromatin Chromatin Modeling Chromatin Structure Clinical Code Collection Complex DNA DNA Binding DNA Modification Process DNA Sequence DNA-Binding Proteins Development Diagnosis Discrimination Disease Epigenetic Process Event Genetic Transcription Genomics Glean Goals Histones In Vitro Length Mediating Methyl-CpG-Binding Protein 2 Modeling Modification Molecular Mutation Mutation Analysis Names Nature Neurons Nucleosomes Nucleotides Phase Play Property Proteins Publishing RNA Splicing Research Rett Syndrome Role Site Specificity Structure Structure-Activity Relationship Tissues X Chromosome autism spectrum disorder base cell behavior chromatin protein developmental disease disability genetic regulatory protein in vivo insight mutant nervous system disorder neuron development neuronal metabolism novel programs tool virtual

项目摘要

Abstract The X chromosome coded `Methyl CpG binding protein 2' (MECP2) is highly expressed in neuronal tissues and named for its recognition of the methyl-CpG (mCpG) epigenetic modification. The importance of MeCP2 to neuronal and brain development is highlighted by the fact that MeCP2 mutations cause >90% of the diagnosed cases of the autism spectrum disorder Rett syndrome. Recent genomic studies have raised important questions regarding the full range of DNA sequences and types of base modifications bound by the protein. Our proposed studies seek to determine the molecular mechanisms underlying specific recognition of the type of nucleotide modification, DNA sequence, and binding cooperativity that meld to mediate localization of MeCP2 on chromatin. Our project interleaves energetic and structural analyses proposing quantitative assembly studies to determine the combinations of nucleotide modification with local and flanking DNA sequences that confer high specificity MeCP2 binding, the structure of MeCP2 - DNA complexes to reveal if differences exist among the bound target sites, and determine how MeCP2 competes with linker histones on chromatin and subsequently localizes to specific sites. Our proposal integrates established and novel quantitative and structural approaches to explore how binding of this key regulatory protein to chromatin initiates a cascade of molecular interactions that guides neuronal development.

抽象的 X染色体编码的“甲基CpG结合蛋白2”（MECP2）在神经元中高度表达组织并以其对甲基-CPG（MCPG）表观遗传修饰的认识而得名。这 MECP2强调了MECP2对神经元和大脑发育的重要性突变导致> 90％的自闭症谱系障碍综合征的诊断病例。最近的基因组研究提出了有关DNA序列的全部范围的重要问题以及由蛋白质结合的碱基修饰的类型。我们提出的研究旨在确定对核苷酸修饰类型DNA的特定识别的分子机制序列和结合合作社介导了MECP2在染色质上的定位。我们的项目交通充满活力和结构分析，提出定量组装研究确定核苷酸修饰与局部和侧翼DNA序列的组合，该序列赋予高特异性MECP2结合，MECP2 -DNA复合物的结构有限目标站点之间存在差异，并确定MECP2如何与链接器竞争染色质上的组蛋白，随后将其定位于特定位点。我们的建议整合建立的新颖定量和结构方法，以探索该密钥的结合如何调节蛋白染色质启动一系列分子相互作用，引导神经元发展。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ca(II) and Zn(II) Cooperate To Modulate the Structure and Self-Assembly of S100A12.

Ca(II) 和 Zn(II) 协同调节 S100A12 的结构和自组装。

DOI：
10.1021/acs.biochem.9b00123
发表时间：
2019
期刊：
Biochemistry
影响因子：
2.9
作者：
Wang,Qian;Aleshintsev,Aleksey;Bolton,David;Zhuang,Jianqin;Brenowitz,Michael;Gupta,Rupal
通讯作者：
Gupta,Rupal