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

• 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
• 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

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.

摘要

项目成果

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