Regulating retinal gene expression in three-dimensional nuclear space

描述(由申请人提供)：越来越多的证据表明，基因组的动态和非随机的三维(3D)组织在平衡基因转录方面的重要性。基因表达需要在数量水平上保持平衡，因为基因表达不平衡会导致细胞内生化失衡，最终导致细胞损伤甚至死亡。事实上，最近发现老年性黄斑变性(AMD)严重破坏了基因表达的平衡。此外，在早衰症和各种类型的癌症中，核结构的异常也被观察到与基因组不稳定和基因表达不平衡有关。尽管最近取得了进展，但关于染色质组织是如何动态调节的，以及如何需要这种调节来确保基因表达的数量平衡，我们仍然有很多需要了解的东西。为了帮助弥合这一知识鸿沟，我们建议在斑马鱼视网膜的视锥感光核中定位一些表达水平和功能不同的代表性基因的3D位置。这些定位研究将揭示这些基因的表达活性与它们在光感受器核中的空间定位之间的功能关系。这个 这一建议的目的是在全球水平上确定锥体细胞的3D核结构是如何组织的，以促进选择性和定量平衡的基因表达。结果是 这项研究将为未来的研究奠定基础，以实现我们的长期目标 了解核结构如何通过平衡视网膜基因表达在维持视网膜健康以及防止视网膜退化方面发挥作用。

DESCRIPTION (provided by applicant): Growing evidence demonstrates the essentiality of the dynamic and nonrandom 3-dimensional (3D) organization of the genome in balancing gene transcription. Gene expression needs to be balanced at quantitative levels because imbalanced gene expression leads to a biochemical imbalance in the cells, which eventually leads to cellular damages or even death. In fact, it was recently found that age-related macular degeneration (AMD) severely disrupts the balance of gene expression. In addition, abnormalities in nuclear architecture have been observed to be involved in genomic instability and imbalanced gene expression in progeria and various types of cancer. Despite the recent progress, we still have much to understand about how chromatin organization is dynamically regulated as well as how such regulations are required to ensure quantitatively balanced gene expression. In an effort to help close this knowledge gap, we here propose to map the 3D positions of some representative genes of different expression levels and functions in the cone photoreceptor nuclei in the zebrafish retina. These mapping studies will reveal functional relationships between the expression activities of these genes and their spatial positioning in photoreceptor nuclei. The aim of this proposal is to determine at the global level how the 3D nuclear architecture of cone cells is organized to facilitate selective and quantitatively balanced gene expression. The results of this research will establish a foundation for future research to achieve our long term objective to understand how the nuclear architecture plays a role in maintaining retinal health as well as preventing retinal degeneration by balancing retinal gene expression.