Grant: Fellowship: Bisby (Prize)

Liver X nuclear receptors (LXRs) are important regulators of macrophage activity, a key cell type of the immune system, and have been implicated in the development of many inflammatory human diseases, including atherosclerosis. One of the most potent properties of LXRs is their ability to inhibit expression of pro-inflammatory genes. However, the inhibitory mechanisms activated by LXRs are not fully understood. Interestingly, a recent study by the Glass lab discovered numerous potential sites in the genome of macrophages lying outside gene sequences that could mediate LXR - DNA interactions. Interestingly, these non-coding regions of DNA, called enhancers, appear to play a critical role in organizing the 3D structure of DNA, which in turn regulates gene expression. As highly precise and coordinated spatial re-organizations of DNA are required to achieve efficient pro-inflammatory gene expression, we hypothesize that activated LXRs bind to DNA in enhancer regions and subsequently interfere with such DNA re-organization, thus resulting in an impairment of gene expression. The investigation of this hypothesis is the primary aim of this project, and will require the use of the latest state-of-the-art technologies in epigenetics and bioinformatics. These will be used to monitor the precise DNA spatial re-organizations that are required for the expression of pro-inflammatory gene interleukin 1 beta, which will be assessed in macrophages in the presence or absence of activated LXRs. The specific enhancers involved in those re-organizations will also be further characterized at the molecular level. This work will provide critical insights into the anti-inflammatory mechanisms activated by LXRs that inhibit pro-inflammatory gene expression. As such, it will contribute key knowledge for the design of better diagnostic and therapeutic protocols for atherosclerosis and other inflammatory diseases.