Grant: Project Grant

Our genes are arranged on large pieces of DNA called chromosomes. Chromosomes are huge molecules that must undergo multiple levels of compaction to fit into the cell. At the same time, the genes characteristic of that cell type must remain accessible for activation. In a stem cell the chromosomes are loosely packaged and many genes are poised for activation. When the stem cell commits to becoming a specific cell type (eg. neuron) it must tightly package and silence those genes that are not required and fully activate those genes that will be turned on. To do this cells have developed a complex series of proteins to control the structure of chromosomes and the regulation of genes. When this process is defective, cells cannot divide, differentiate or initiate gene expression effectively. Recent work has shown that mutations in chromosome regulating proteins cause a variety of human diseases, including developmental disorders with severe intellectual disability and numerous types of cancer. This project studies the ATRX gene that, when mutated, causes a severe intellectual disability syndrome. Despite our success in identifying these genes, our understanding of how these chromosome regulatory proteins coordinate which genes to turn on or off, when to turn them on or off, and in what order remains poorly defined. This project aims to define the function of ATRX during brain development, learning, and memory formation by studying a mouse model in which the ATRX gene has been inactivated. Since many of these changes to our chromosomes are dynamic and reversible we will also explore whether we can rescue the phenotypic features of the disease by adding back a normal copy of the gene. With our current ability to use viruses to re-introduce genes to kill cancer cells and clinical trials underway to use them to treat neuromuscular disease, the possibility that they could be used to treat a devastating intellectual disability is promising and provides immense hope.