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.
This study will utilize the zebrafish retina as a model system to study the functional correlation between gene expression levels and gene positioning in the 3-dimensional nuclear space in the retinal photoreceptors. The results of this study will provide entry points for future investigations to unravel the roles of the nuclear structure in retinal cel health by maintaining balanced gene expression, which can be disrupted in many retinal degenerative diseases such as age-related macular degeneration. Because retinal degenerative conditions affects millions of people, our research will potentially have a significant impact on public health.