Grant: Operating Grant

All of our genes are arranged on large pieces of DNA called chromosomes. The 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 manage this process 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. Indeed, 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. Despite this success, 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. The main aim of this research is to delineate the roles of two closely related chromosome organizing proteins, Snf2h and Snf2l that appear to have complementary roles on neural stem cell function during brain development. Defining this fundamental process is critical for us to understand how a stem cell commits to a specific cell fate and how it maintains an organized chromosome. A thorough understanding of these processes is a prerequisite to determining how these complex disorders develop, progress, and for engineering novel treatment strategies.