Mechanisms of Epigenetic inheritance

表观遗传机制

• 批准号: 9751887
• 负责人: Zhiguo Zhang
• 金额: $ 81.19万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751887
• 关键词: Binding Proteins; Biochemical; Cell Cycle; Cell division; Cells; Chromatin; Chromatin Structure; Complex; Coupled; DNA; DNA Repair; DNA biosynthesis; DNA replication fork; Defect; Development; Epigenetic Process; Gene Silencing; Genes; Genetic; Genomic Instability; Genomic approach; Heterochromatin; Higher Order Chromatin Structure; Histone H3; Human; Inherited; Malignant Neoplasms; Mammalian Cell; Methods; Mitotic; Molecular; Monitor; Mutation; Nucleosomes; Peptide Sequence Determination; Play; Process; Proteins; RNA; Role; S Phase; Time; Yeasts; daughter cell; genome integrity; histone modification; insight; novel; public health relevance; transmission process

 DESCRIPTION (provided by applicant): How epigenetic states are inherited during S phase of the cell cycle is one of the most challenging questions in the chromatin and epigenetic fields. DNA replication-coupled nucleosome assembly plays an important role in epigenetic inheritance following DNA replication and DNA repair. Mutations of most, if not all, genes involved in replication-coupled nucleosome assembly result in defects in transcriptional silencing at heterochromatin and genome instability in both yeast and mammalian cells. We have been studying how nucleosomes are formed following DNA replication in yeast and human cells and have made multiple significant contributions to this process. However, how parental histone (H3-H4)2 tetramers are transferred to replicating DNA is still poorly understood, which hinders our understanding of transmission of epigenetic information into daughter cells. The major challenge to understanding parental histone (H3-H4)2 assembly is a lack of methods to track this process. Despite this challenge, we have developed the eSPAN (enrichment and Sequencing Protein- Associated Nascent DNA) method that can discern whether a protein binds to leading or lagging strands of DNA replication forks. This method enables us for the first time to monitor nucleosome assembly of both newly synthesized and parental histone (H3-H4)2 onto leading and lagging strands of DNA replication forks. In this proposal, we will elucidate molecular mechanisms whereby parental (H3-H4)2 are assembled into nucleosomes following DNA replication and how epigenetic marks are inherited during mitotic cell division in both yeast and human cells using a combination of genetic, biochemical and genomic approaches. Together, our studies should have a profound impact on the understanding of nucleosome assembly and epigenetic inheritance.