Non-canonical functions of chromatin insulators and Polycomb-group proteins

染色质绝缘体和多梳族蛋白的非规范功能

• 批准号: 10437937
• 负责人: JAMES B JAYNES
• 金额: $ 31.2万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437937
• 关键词: 3-Dimensional; Address; Adult; Affect; Aging; Architecture; Binding; Binding Proteins; Biochemical; Biochemical Genetics; Biological; Biological Assay; Cell Nucleus; Cells; Chromatin; Chromatin Structure; Chromosome Structures; Chromosomes; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Binding; Data; Development; Diagnosis; Disease; Dosage Compensation (Genetics); Drosophila genus; Effectiveness; Elements; Embryo; Embryonic Development; Enhancers; Epigenetic Process; Exhibits; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic study; Genome; Hereditary Disease; Human; Inherited; Intervention; Laboratories; Maintenance; Mammals; Mediating; Memory; Names; Neuraxis; Nuclear; Organism; Poly A; Polycomb; Prevention; Process; Promoter Regions; Proteins; Reading; Regulation; Regulator Genes; Repression; Response Elements; Signal Transduction; Sorting - Cell Movement; System; Test Result; Testing; Tissues; Transcript; Transgenic Organisms; Work; base; chromatin immunoprecipitation; chromatin modification; chromatin protein; diagnostic tool; effective intervention; experimental study; genetic approach; genome-wide; genome-wide analysis; histone modification; human disease; in vivo; insight; novel; novel strategies; promoter; protein complex; stem cells; tool; transcription factor; tumor progression; tumorigenesis

Changes in gene transcription are important in the progression of cancer, in most other human diseases, and in the aging process, as well as in the development of multicellular organisms at all stages. A full understanding of how such changes are regulated is the basis of diagnostic tools and intervention strategies. Further advancement holds the promise of novel approaches, and of increased effectiveness of current approaches. Tools available in Drosophila make it possible to study gene regulatory mechanisms in great detail, in a true in vivo context. This proposal is to study mechanisms of chromatin-based gene regulation involving Polycomb-response elements (PREs) and insulators (including one named homie) that are found in the well-characterized Drosophila gene even skipped. These studies will address basic questions of how regulatory DNA that mediates transcriptional memory and chromosome organization carries out its function in 3 dimensions in the nucleus. They will provide a clearer understanding of how epigenetic mechanisms propagate alternative transcriptional states, and how chromosomal domain organization affects gene expression. A unique contribution of these studies is to integrate these mechanisms with those mediating enhancer-promoter interactions in a developmental context. In mammals, Polycomb-group proteins and insulators are involved in the maintenance of stem cell identity, developmental decisions, and dosage compensation, as well as in oncogenesis and inherited human disorders. The Specific Aims are: Aim 1. Determine how the conserved, DNA binding Polycomb-group (PcG) protein Pleiohomeotic (Pho) maintains both the active and the repressed state of Drosophila even skipped (eve) gene expression. Determine how novel epigenetic mechanisms that regulate eve are deployed genome-wide. Results from these studies will propel the field of epigenetic gene regulation into novel territory, uncovering entirely new influences on both development and adult tissue maintenance. Aim 2. Determine how read-through transcription represses enhancer function and how this repression is influenced by Polycomb domains, at eve and throughout the genome. Studies here will explore a new way in which the very act of transcription regulates genes, leading to mechanistic insights that apply genome-wide. Aim 3. Determine mechanisms whereby some promoters initiate highly processive transcription that reads through barriers, such as poly(A) addition signals, while others do not. Processive transcription has the power to influence gene expression and chromosome architecture over great distances along a chromosome. Its regulation and influence are just beginning to be understood. We have developed a sensitive assay system that will allow us to make rapid progress toward a mechanistic understanding.

基因转录的变化在癌症和大多数其他人类疾病的进展中都很重要