Histone Demethylases and Their Regulation

组蛋白去甲基化酶及其调控

• 批准号: 8297242
• 负责人: Yujiang Geno Shi
• 金额: $ 33.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297242
• 关键词: Binding; Biochemical; Biological; Biological Assay; Biology; Calorimetry; Cells; Chromatin; Clinical; Deletion Mutation; Development; Disease; Epigenetic Process; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Histones; Human; In Vitro; Knowledge; Link; Lysine; Malignant Neoplasms; Mediating; Mission; Modification; Molecular; Names; Nuclear Protein; Nucleosomes; Outcome; PWWP Domain; Peptides; Process; Proteins; Public Health; Recombinants; Recruitment Activity; Regulation; Research; Role; Site; Testing; Therapeutic; TimeLine; Titrations; Translational Research; base; cofactor; demethylation; histone modification; in vitro Assay; in vivo; insight; promoter; research study

This proposal investigates how histone lysine demethylase LSD2 is targeted and retained to actively transcribed gene bodies by its cofactor NPAC. We hypothesize that NPAC has dual interactions with LSD2 via NPAC's linker region and the H3K36me3 histone modification- containing nucleosomes via NPAC's PWWP domain, thereby physically linking LSD2 to H3K36me3-enriched functional sites. We will employ various NPAC mutation and deletion constructs and use molecular biological and biochemical approaches to determine the molecular mechanism underlying NPAC-mediated targeting of LSD2 to its functional sites. Results from the proposed study will offer significant insight into the molecular mechanism by which NPAC contributes to LSD2 mediated gene regulation within actively transcribed gene bodies. If successful, the proposal is expected to offer new insight into our understanding of the role and mechanism of action of cofactors in regulation of histone demethylation, and make significant impact on the advancement of epigenetic gene regulation and chromatin biology. Ultimately, findings from the proposed study will also provide important information for the development of epigenetic-based therapeutics.

该提案研究了组蛋白赖氨酸脱甲基酶LSD 2如何靶向和保留， 通过其辅因子NPAC活跃地转录基因体。我们假设NPAC具有双重 通过NPAC的连接区和H3 K36 me 3组蛋白修饰与LSD 2相互作用- 通过NPAC的PWWP结构域包含核小体，从而将LSD 2物理连接到 H3 K36 me 3富集的功能位点。我们将采用各种NPAC突变和缺失 构建并使用分子生物学和生物化学方法来确定 NPAC介导的LSD 2靶向其功能位点的分子机制。 从拟议的研究结果将提供重要的深入了解分子机制， 其中NPAC有助于LSD 2介导的活跃转录基因内的基因调控， 尸体如果成功的话，该提案有望为我们理解 辅助因子在调节组蛋白去甲基化中的作用和机制， 对表观遗传基因调控和染色质生物学的进步产生重大影响。 最终，拟议研究的结果也将为 基于表观遗传学的治疗方法的发展。

项目成果

Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells.

• DOI: 10.1016/j.molcel.2011.04.005
• 发表时间: 2011-05-20
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Xu Y;Wu F;Tan L;Kong L;Xiong L;Deng J;Barbera AJ;Zheng L;Zhang H;Huang S;Min J;Nicholson T;Chen T;Xu G;Shi Y;Zhang K;Shi YG
• 通讯作者: Shi YG