DNA is highly organized within the nucleus of each cell. DNA loops bring together genes and regulatory elements that are distant along the linear dimension of DNA, allowing regulatory interactions that modulate gene expression. The cohesin complex is a ubiquitously expressed mediator of DNA looping interactions. This complex has a critical role in development;mutations that slightly reduce the levels of cohesin complex subunits or cohesin regulatory proteins cause human developmental syndromes collectively dubbed cohesinopathies. These syndromes are characterized by developmental malformations and mental retardation. Despite its importance, the precise role of cohesin and the mechanisms that regulate its function are unknown. The purpose of the proposed project is to determine how cohesin controls gene expression and nuclear organization over the course of development and to better understand how loss of cohesin function affects development. This project will examine cohesin function in mouse olfactory sensory neurons, which constitute a well characterized and experimentally tractable model for neural development. Experiments on cells at defined stages of differentiation will identify developmentally regulated cohesin binding sites and DNA looping interactions that are controlled by cohesin recruitment. The functional role of cohesin in regulating gene expression and nuclear organization in mature OSNs will be determined by deleting cohesin, or the complex that loads cohesin onto DNA, specifically in these cells. Together these experiments will yield new insight into the central role of cohesin in patterning gene expression over development.
DNA organization within the nucleus is critical for the specialized patterns of gene expression that allow cells to serve different functions within the body. Mutations affecting a protein complex that controls DNA organization cause human developmental disorders. This proposal will study this protein complex in a model developmental system in order to determine how it regulates changes in DNA organization required for development.