Chromatin Remodeling Complex in the spreading of silent heterochromatin

沉默异染色质传播中的染色质重塑复合物

• 批准号: 8118739
• 负责人: Kevin Michael Creamer
• 金额: $ 3.14万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2014-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118739
• 关键词: Acceleration; Age; Aging; Binding; Biochemical; Biochemistry; Cell Aging; Cell Survival; Cell physiology; Cells; Centromere; Chromatin; Chromatin Remodeling Factor; Complex; DNA Damage; Data; Deacetylation; Defect; Disease; Epigenetic Process; Fission Yeast; Gene Expression; Gene Mutation; Genetic; Genetic Transcription; Genomics; Heterochromatin; Histone Deacetylase; In Vitro; Lead; Mediating; Methods; Microtubules; Molecular; Normal Cell; NuRD complex; Nucleosomes; Premature aging syndrome; Proteins; Role; Saccharomycetales; Therapeutic Intervention; base; cell age; chromatin remodeling; histone modification; in vitro activity; interest; yeast genetics

DESCRIPTION (provided by applicant): Ageing, either natural or disease-driven, is accompanied by global epigenetic changes including the disruption of silent heterochromatin. Recently, a physical and functional connection has been made between the chromatin changes that occur as cells age and the NuRD chromatin remodeling complex. NuRD is a unique chromatin modifying complex in that it harbors the physical association of histone deacetylase as well as nucleosome remodelling activity. While seemingly absent from budding yeast, a highly similar complex, SHREC, has been purified from the fission yeast S. pombe which appears to regulate heterochromatin in a manner similar to mammalian NuRD. This proposal seeks to investigate the molecular and biochemical basis for SHREC- dependent spreading of heterochromatin using the tractability of yeast genetics and in vitro biochemistry with the intent of characterizing the importance of conserved chromatin binding modules as well as activity of the complex in modifying nucleosomal substrates. PUBLIC HEALTH RELEVANCE: As cells age, they accumulate chromatin defects that lead to DNA damage and alteration of gene expression. Determining the precise mechanisms regulating these epigenetic changes should prove useful in the understanding and possible therapeutic intervention of normal and hyper-accelerated ageing.

描述（由申请人提供）：衰老，无论是自然的还是疾病驱动的，都伴随着全球表观遗传变化，包括沉默异染色质的破坏。最近，一个物理和功能之间的连接已经发生的染色质变化，细胞老化和NuRD染色质重塑复合物。NuRD是一种独特的染色质修饰复合物，因为它具有组蛋白脱乙酰酶的物理缔合以及核小体重塑活性。虽然在芽殖酵母中似乎不存在，但已经从裂殖酵母S中纯化出高度相似的复合物SHREC。粟酒裂殖酵母似乎以类似于哺乳动物NuRD的方式调节异染色质。该提案旨在利用酵母遗传学和体外生物化学的易处理性研究异染色质的SHREC依赖性扩散的分子和生物化学基础，旨在表征保守的染色质结合模块的重要性以及复合物在修饰核小体底物中的活性。 公共卫生相关性：随着细胞老化，它们积累染色质缺陷，导致DNA损伤和基因表达改变。确定调节这些表观遗传变化的精确机制，应该证明是有用的理解和可能的治疗干预正常和超加速老化。