Intra- and inter-cluster regulations of multiplex gene clusters

多重基因簇的簇内和簇间调控

• 批准号: 10715806
• 负责人: Ya-Chen Liang
• 金额: $ 41.25万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715806
• 关键词: 3-Dimensional; Biological; Birds; Cell Nucleus; Chromatin Loop; Chromosome Mapping; Chromosomes; Complex; DNA Sequence; Development; Disease; Epigenetic Process; Gene Cluster; Gene Expression Regulation; Gene Family; Gene Order; Gene Structure; Genes; Genetic Transcription; Genome; Genomics; Globin; Heterogeneity; Homeostasis; Homologous Gene; Human; Keratin; Knowledge; Molecular; Molecular Conformation; Morphogenesis; Mus; Mutation; Organ; Outcome; Pattern; Proteins; Regulation; Research; Structure; Tissues; Transcriptional Regulation; chromatin protein; insight; novel; olfactory receptor; skin organogenesis; two-dimensional

Project Summary A gene cluster is a group of two or more homologous genes arranged within a certain genomic range. These gene clusters are widespread in genomes across species. They account for 22% and 18% of annotated genes in mice and humans, respectively. A gene family usually contains multiple gene clusters located on different chromosomes. Therefore, studying the regulation of gene clusters adds a new layer on top of traditional tran- scriptional regulation. Studies on the Keratin, Hox, Globin, Olfactory-Receptor, and other gene clusters revealed distinct epigenetic and topological states that contribute to differential transcriptional outcomes. The knowledge gaps in the field are: (i) missing detailed mechanistic machinery that constitutes specific epigenetic and topolog- ical domains on a gene cluster, (ii) is there general interchromosomal crosstalk of multiplex gene clusters in the same gene family, and (iii) what protein modules spatially organize gene clusters in the cell nucleus and facilitate their coordination. The proposed research seeks to decompose (a) epigenetic principles of gene clusters with distinct expression patterns, (b) molecular mechanisms that configure intra- and inter-cluster conformations, and (c) protein cascades that organize gene clusters within sub-nuclear structures. We will utilize the multiplex Ker- atin gene clusters as a paradigm in the biological context of avian skin development. Since gene clusters are widespread in genomes and used in novel development and organ morphogenesis, misexpression or mutation of clustered genes contributes to abnormal development and diseases. The proposed research will provide a fundamental understanding of complex gene regulation. It will also extend our previous insights of localized gene regulation to how spatial subnuclear compartmentation facilitates transcriptional heterogeneity of compound genes during tissue development and homeostasis.

项目概要 基因簇是在一定基因组范围内排列的两个或多个同源基因的集合。这些 基因簇广泛存在于各个物种的基因组中。它们分别占注释基因的 22% 和 18% 分别在小鼠和人类中。一个基因家族通常包含位于不同位置的多个基因簇 染色体。因此，研究基因簇的调控在传统的转录基础上又增加了一个新的层次。 脚本性规定。对角蛋白、Hox、球蛋白、嗅觉受体和其他基因簇的研究表明 不同的表观遗传和拓扑状态导致不同的转录结果。知识点 该领域的差距是：（i）缺少构成特定表观遗传和拓扑结构的详细机制。 基因簇上的 ical 结构域，(ii) 是否存在多重基因簇的一般染色体间串扰 相同的基因家族，以及（iii）哪些蛋白质模块在细胞核中空间组织基因簇并促进 他们的协调。拟议的研究旨在分解（a）基因簇的表观遗传原理 不同的表达模式，（b）配置簇内和簇间构象的分子机制，以及 (c) 在亚核结构内组织基因簇的蛋白质级联。我们将利用多路复用 Ker- atin基因簇作为鸟类皮肤发育生物学背景的范例。由于基因簇是 广泛存在于基因组中并用于新的发育和器官形态发生、错误表达或突变 聚集的基因会导致异常发育和疾病。拟议的研究将提供 对复杂基因调控的基本了解。它还将扩展我们之前对局部基因的见解 调控空间亚核区室如何促进化合物的转录异质性 组织发育和稳态过程中的基因。