Biochemical dissection of epigenetic inheritance by Polycomb group proteins.

多梳族蛋白对表观遗传的生化剖析。

• 批准号: 7812193
• 负责人: Nicole Jane Francis
• 金额: $ 45.36万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812193
• 关键词: Address; Affect; Behavior; Binding; Binding Sites; Biochemical; Biological Assay; Body Patterning; Cell Cycle; Cell division; Cell physiology; Cells; Chimeric Proteins; Chromatin; Chromatin Structure; Chromosomes; Colchicine; Complex; DNA biosynthesis; Data; Development; Disease; Dissection; Drosophila genus; Epigenetic Process; Event; Face; Fractionation; Gene Expression; Gene Expression Regulation; Genes; Genetic Programming; Hematopoietic; Hypersensitivity; Image; Inherited; Malignant Neoplasms; Mammals; Mediating; Mitosis; Mitotic; Mitotic Chromosome; Modeling; Molecular Conformation; Normal Cell; Oncogenes; Organism; Outcome; Pattern; Polycomb; Protein Binding; Proteins; Regulator Genes; Response Elements; Stem cells; Testing; Tumor Suppressor Proteins; Western Blotting; X Inactivation; base; cell type; chromatin immunoprecipitation; interest; programs; protein complex; protein distribution; protein function; public health relevance; relating to nervous system; tumor progression

DESCRIPTION (provided by applicant): Epigenetic mechanisms make gene expression patterns stable by maintaining gene regulatory information through cell divisions. Proteins encoded by the Drosophila Polycomb Group (PcG) genes maintain key patterns of gene expression during development, likely through heritable alterations to chromatin structure. PcG genes and their functions are conserved in mammals where they are also misregulated in cancer, and associated with tumour progression. During the cell cycle, chromatin-based epigenetic information faces two challenges, DNA replication and mitosis. In our original proposal, we addressed how PcG-dependent gene regulation may be inherited through DNA replication. The revision aims address how PcG effects can be inherited through mitosis. During mitosis, chromosomes undergo dramatic structural and biochemical changes, including the loss of many gene regulatory factors. For chromatin based gene regulatory information to be maintained through mitosis, regulators must either remain associated with mitotic chromatin or mark the chromatin to direct their return. To determine whether PcG proteins themselves could transmit gene regulatory information through mitosis, we will determine what fraction of PcG proteins is retained on chromosomes in mitosis. To understand how chromatin binding by PcG proteins can be maintained or disrupted during mitosis, we will ask whether specific proteins associate with PcG complexes during mitosis, and whether proteins present in extracts from mitotic cells affect the activity of PcG proteins. How PcG proteins behave during mitosis and how this behavior is regulated is important for understanding how PcG-dependent gene regulation is maintained through mitosis, and may have more general implications for epigenetic mechanisms. PUBLIC HEALTH RELEVANCE: Epigenetic mechanisms help maintain cell identities through development by making patterns of gene expression stable. Polycomb proteins are epigenetic regulators of development and are upregulated in many cancers, and are specifically correlated with aggressive cancer progression and poor outcome. This study aims to understand how these proteins function during normal cell division. This will help understand how disruption of their function can occur and how it contributes to tumour progression.

描述（由申请人提供）：表观遗传机制通过细胞分裂维持基因调控信息，使基因表达模式稳定。果蝇多梳族 (PcG) 基因编码的蛋白质在发育过程中维持基因表达的关键模式，可能是通过染色质结构的遗传改变。 PcG 基因及其功能在哺乳动物中是保守的，在癌症中它们也被错误调节，并与肿瘤进展相关。在细胞周期中，基于染色质的表观遗传信息面临两个挑战：DNA 复制和有丝分裂。在我们最初的提案中，我们讨论了 PcG 依赖性基因调控如何通过 DNA 复制遗传。此次修订的目的是解决 PcG 效应如何通过有丝分裂遗传。在有丝分裂期间，染色体经历剧烈的结构和生化变化，包括许多基因调控因子的丧失。用于基于染色质的基因调控信息 为了通过有丝分裂维持，调节因子必须要么与有丝分裂染色质保持联系，要么标记染色质以指导它们的返回。为了确定 PcG 蛋白本身是否可以通过有丝分裂传递基因调控信息，我们将确定有丝分裂中 PcG 蛋白的哪一部分保留在染色体上。为了了解 PcG 蛋白在有丝分裂过程中如何维持或破坏染色质结合，我们将询问特定蛋白质是否在有丝分裂过程中与 PcG 复合物相关，以及有丝分裂细胞提取物中存在的蛋白质是否影响 PcG 蛋白的活性。 PcG 蛋白在有丝分裂过程中如何表现以及如何调节这种行为对于理解如何通过有丝分裂维持 PcG 依赖性基因调节非常重要，并且可能对表观遗传机制具有更普遍的影响。 公共卫生相关性：表观遗传机制通过使基因表达模式稳定来帮助维持细胞在发育过程中的身份。多梳蛋白是发育的表观遗传调节因子，在许多癌症中表达上调，并且与侵袭性癌症进展和不良结果特别相关。这项研究旨在了解这些蛋白质在正常细胞分裂过程中如何发挥作用。这将有助于了解它们的功能如何被破坏以及它如何导致肿瘤进展。