Epigenetic inheritance of heterochromatin

异染色质的表观遗传

• 批准号: 10543528
• 负责人: DANESH MOAZED
• 金额: $ 37.12万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543528
• 关键词: Alleles; Animals; Binding Sites; Biochemical; Biogenesis; Biological Assay; Cells; Chromatin; Chromatin Modeling; Chromosomal Stability; Chromosomes; Complex; Cullin Proteins; DNA biosynthesis; DNA replication fork; DNA-Binding Proteins; Development; Disease Progression; Ensure; Epigenetic Process; Event; Feedback; Fission Yeast; Gene Expression Regulation; Gene Silencing; Genes; Genetic Screening; Genome Stability; Goals; Heterochromatin; Histone H3; Histones; Homeostasis; Human; In Vitro; Inherited; Intervention; Knowledge; Laboratories; Lysine; Maintenance; Mammals; Mediating; Methylation; Methyltransferase; Modeling; Molecular; Molecular Conformation; Mutation; Organism; Pathway interactions; Play; Process; Proteins; RNA; RNA Decay; RNA Degradation; RNA Interference; RNA Processing; Regulation; Ribosomal RNA; Ribosomes; Role; Site; System; Testing; Therapeutic; Ubiquitination; Untranslated RNA; Work; Yeasts; daughter strand; demethylation; design; genetic approach; in vivo; insight; model organism; mutant; protein complex; recruit; transcription factor; transcription termination; ubiquitin ligase

Project Summary The long-term goal of this work is to understand how histone H3 lysine 9 methylation (H3K9me) and heterochromatic gene silencing are epigenetically inherited. Heterochromatin is a conserved feature of eukaryotic chromosmes and plays important roles in regulation of gene expression and maintenance of chromosome stability in organisms ranging from yeast to human. Using the fission yeast Schiozosaccharomyces pombe as a model organism, we recently demonstrated that ectopically induced domains of H3K9me and silencing can be epigenetically inherited in the absence of sequence-specific recruitment when the rate of H3K9me demethylation is reduced by deletion of the Epe1 anti-silencing factor. In addition, we have discovered that, in wildtype epe1+ cells, small noncoding RNAs (siRNAs) or transcription factor binding sites play critical roles in epigenetic maintenance of H3K9me. More recently, we have uncovered roles for an RNAi-independent RNA decay pathaway, autoregulation of the conserved histone H3K9 methyltransferase, and core replication fork-associated proteins in epigenetic maintenance of heterochromatin. In this proposal we will use a combination of in vivo approaches and biochemical assays to investigate (1) the functions of a newly discovered RNA decay complex, called the rixosome, in epigenetic inheritance, (2) the role of a replication fork-associated chromatin assembly complex in retention of histones and epigenetic inheritance during DNA replication, and (3) the role of a conserved ubiquitin ligase in regulation of H3K9 methylation and accurate heterochromatin formation. The ultimate goal of these studies is a molecular understanding of the mechanisms that epigenetically maintain silent chromatin domains.

项目摘要 这项工作的长期目标是了解组蛋白H3赖氨酸9甲基化（H3K9me）和 异染色质基因沉默是表观遗传。异染色质是一个保守的特征， 真核细胞染色体的基因表达调控和维持的重要作用， 从酵母到人类的生物体中的染色体稳定性。利用裂变酵母 粟酒裂殖酵母作为模式生物，我们最近证明异位诱导， H3K9me和沉默的结构域可以在缺乏序列特异性的 当H3K9me去甲基化的速率通过Epe 1抗沉默因子的缺失而降低时的募集。在 此外，我们发现，在野生型epe1+细胞中，小的非编码RNA（siRNA）或转录 因子结合位点在H3K9me的表观遗传维持中起关键作用。最近，我们有 揭示了一个独立于RNAi的RNA衰变途径的作用，保守组蛋白的自动调节 H3K9甲基转移酶和核心复制叉相关蛋白在表观遗传维持中的作用 异染色质在本提案中，我们将使用体内方法和生化测定的组合， 研究（1）一种新发现的RNA衰变复合物的功能，称为rixosome，在表观遗传学中 遗传，（2）复制叉相关染色质组装复合物在组蛋白保留中的作用 和DNA复制过程中的表观遗传，以及（3）保守的泛素连接酶在调控中的作用 H3K9甲基化和准确的异染色质形成。这些研究的最终目标是 对表观遗传学上保持沉默的染色质结构域的机制的分子理解。