Intra- and inter-cluster regulations of multiplex gene clusters

项目摘要 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组。这些 基因簇广泛存在于物种的基因组中。它们分别占注释基因的22%和18% 分别在小鼠和人类身上。一个基因家族通常包含多个基因簇， 染色体因此，研究基因簇的调控在传统的转基因技术上增加了一个新的层次。 脚本规则。对角蛋白、Hox、珠蛋白、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，有助于不同的转录结果。知识 该领域的差距是：（i）缺少构成特定表观遗传和拓扑学的详细机械机制， （ii）在基因簇上的多重基因簇中是否存在一般的染色体间串扰， 相同的基因家族，以及（iii）什么蛋白质模块在空间上组织细胞核中的基因簇并促进 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）构成簇内和簇间构象的分子机制，和 (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克尔- atin基因簇作为鸟类皮肤发育生物学背景下的范例。由于基因簇是 广泛存在于基因组中，用于新的发育和器官形态发生、错误表达或突变 基因簇的分裂导致发育异常和疾病。这项研究将提供一个 对复杂基因调控的基本理解。这也将扩展我们以前对局部基因的认识， 调节亚核空间区室化如何促进化合物的转录异质性 基因在组织发育和体内平衡中的作用。

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.