Eukaryotes contain thousands of genes whose unique patterns of expression establish distinct cellular identities. Within the nucleus, genes reside within chromosomes that localize to distinct nuclear territories to facilitate regulation of gene expression. Our lab is interested in understanding how nuclear organization contributes to transcriptional control through two lines of investigation. Our studies use molecular and genetic approaches, using Drosophila as a model system.
First, we study the molecular mechanism of a class of conserved DNA elements known as insulators. These elements establish independent transcriptional domains within chromosomes. Insulators play a critical role in many developmental processes, such as imprinting and mammalian dosage compensation. Loss of insulator function is associated with genome instability, as evidenced in congenital forms of myotonic dystrophy. Our studies focus on the Drosophila Suppressor of Hairy-wing [Su(Hw)] insulator protein. Loss of this protein causes female sterility, due to a block in germ line development. We are defining the role of the Su(Hw) insulator protein in oogenesis to understand how insulator proteins contribute to nuclear functions in development.
Second, we investigate regulatory contributions of the nuclear lamina, protein meshwork underneath the nuclear envelope (NE) that contributes to chromosome organization and gene regulation. Our studies are directed LEM domain (LEM-D) proteins, a class of lamina proteins that bind Barrier-to-Autointegration Factor (BAF). Through interactions with BAF, LEM-D proteins bring chromosomes to the nuclear periphery to establish chromosomal territories. Although LEM-D proteins are globally expressed, loss of these proteins causes tissue-restricted diseases, such as Emery-Dreifuss muscular dystrophy (EDMD), cardiomyopathies and bone density disorders. The Drosophila genome encodes four LEM-D proteins that make unique and overlapping contributions to development. We find that loss of these proteins disrupts key developmental signaling cascades, with evidence for a role in stem cell homeostasis. We are defining how LEM-D proteins regulate nuclear lamina function to understand the role of these proteins in developmental processes that include maintenance of stem cell function.