Molecular mechanisms of gene silencing by H4 methylation

H4甲基化基因沉默的分子机制

基本信息

批准号：
7894449
负责人：
JUDD C RICE
金额：
$ 30.47万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7894449
关键词：
Amino Acids Autoimmune Diseases Binding Binding Proteins Biochemical Biological Process Cell Lineage Cell Nucleus Cell division Cells Data Defect Development Differentiation and Growth Disease Enzymes Essential Genes Figs - dietary Future Gene Activation Gene Expression Gene Expression Regulation Gene Silencing Gene Silencing Pathway Gene Targeting Genes Goals Growth Health Hematopoiesis Histone Code Histone H3 Histone H4 Histones Human In Vitro Individual Investigation Lead Life Lysine Mediating Methods Methylation Methyltransferase Molecular Normal Cell Pathway interactions Play Post-Translational Protein Processing Process Property Protein Binding Proteins RUNX1 gene Recruitment Activity Regulation Repression Research Personnel Rice Role Tail Techniques Transcriptional Regulation base gene function gene repression histone modification in vivo in vivo Model leukemia novel prevent programs promoter tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The histone proteins are responsible for the compaction and functional organization of DMA in the nucleus. These small, evolutionary conserved proteins are host to a diverse array of post-translational modifications, each of which is typically associated with a specific DNA-templated process, such as gene regulation. We recently discovered a novel mammalian gene silencing pathway mediated by the PR-Set7 enzyme that specifically monomethylates histone H4 lysine 20 (H4K20). Our new findings indicate that this silencing pathway is targeted to the promoters of certain genes that function in growth and differentiation programs. Based on these findings, our central hypothesis is that one major role of H4K20 monomethylation is to maintain cellular identity by repressing specific sets of genes that promote growth and differentiation. The goal of this proposal is to dissect the molecular mechanisms of this fundamental gene silencing pathway with the long range goal of determining the role of this pathway in establishing and maintaining cellular identity. We recently discovered that PR-Set7 associates with a novel histone H3 lysine 9 (H3K9) methyltransferase to create a repressive monomethyl-H4K20 and H3K9 "trans-tail histone code" at gene promoters. In Aim 1 we will use established molecular and biochemical methods to identify and characterize this enzyme and determine its in vivo role in gene repression. We have also discovered the first known H4K20 monomethyl- binding protein, L(3)MBT, and determined that this interaction is essential for gene repression. In Aim 2 we will define the regions and amino acids of L(3)MBT required for binding monomethylated H4K20 and gene repression. In Aim 3 we will continue to identify additional genes regulated by this silencing pathway. These genes serve as the in vivo models to dissect apart the individual contributions of each of the components of this pathway on in vivo gene repression. Collectively, this proposal will illuminate the molecular mechanisms of a fundamental mammalian gene regulation pathway involved in critical biological processes and will likely have far-reaching and wide-spread impacts on human health and disease.

描述（由申请人提供）：组蛋白负责细胞核中 DMA 的压缩和功能组织。这些进化上保守的小蛋白质是多种翻译后修饰的宿主，每种修饰通常与特定的 DNA 模板过程相关，例如基因调控。我们最近发现了一种由 PR-Set7 酶介导的新型哺乳动物基因沉默途径，该酶特异性单甲基化组蛋白 H4 赖氨酸 20 (H4K20)。我们的新发现表明，这种沉默途径针对的是在生长和分化程序中发挥作用的某些基因的启动子。基于这些发现，我们的中心假设是 H4K20 单甲基化的一个主要作用是通过抑制促进生长和分化的特定基因组来维持细胞身份。该提案的目标是剖析这一基本基因沉默途径的分子机制，长期目标是确定该途径在建立和维持细胞身份中的作用。我们最近发现 PR-Set7 与一种新型组蛋白 H3 赖氨酸 9 (H3K9) 甲基转移酶结合，在基因启动子处创建抑制性单甲基 H4K20 和 H3K9“反式尾组蛋白密码”。在目标 1 中，我们将使用已建立的分子和生化方法来识别和表征这种酶，并确定其在基因抑制中的体内作用。我们还发现了第一个已知的 H4K20 单甲基结合蛋白 L(3)MBT，并确定这种相互作用对于基因抑制至关重要。在目标 2 中，我们将定义结合单甲基化 H4K20 和基因抑制所需的 L(3)MBT 区域和氨基酸。在目标 3 中，我们将继续鉴定受此沉默途径调节的其他基因。这些基因作为体内模型来剖析该途径的每个组成部分对体内基因抑制的单独贡献。总的来说，该提案将阐明参与关键生物过程的基本哺乳动物基因调控途径的分子机制，并可能对人类健康和疾病产生深远而广泛的影响。