Eukaryotes contain thousands of genes whose unique patterns of expression establish distinct cellular identities. These processes require coordinate transcriptional regulation of hundreds of genes. Within the nucleus, genes reside within chromosomes that are arranged in the nucleus to facilitate gene expression. Emerging evidence suggests that nuclear organization of chromosomes is fundamental to transcription regulatory processes, as explified by observations that mutations in the nuclear envelop proteins, such as nuclear lamins, are associated with the human diseases of Emery-Dreifuss muscular dystrophy and the Hutchinson-Gilford progeria syndrome, associated with premature aging. It is believed that these diseases are caused by mis-expression of genes due to changes in nuclear positioning.
Within chromosomes, many clusters of co-expressed genes exist. These functional domains likely facilitate transcriptional regulation, as chromosomal rearrangements that disrupt this organization often influence levels of gene expression. Formation of independent regulatory domains may depend upon a specialized class of DNA elements, known as insulators. Insulators have been identified in most eukaryotic genomes, suggesting a conserved role in defining domains of gene function. Insulators play a critical role in many developmental processes, such as imprinting and mammalian dosage compensation and a loss of insulator function is associated with congenital forms of myotonic dystrophy.
Our laboratory is interested in understanding how chromosome organization impacts gene expression. To this end, we are taking molecular genetic and biochemical approaches to investigate chromosome organization in Drosophila melanogaster. We are engaged in three research areas. First, we are studying the role of nuclear envelope proteins, such as lamins, in gene expression in Drosophila. Second, we are examining the role of a chromatin insulator, known as the gypsy insulator, in defining domains of gene expression. Third, we are studying the process of transvection, where enhancers on one chromosome activate transcription of the paired, homologous promoter. These studies will provide insights into mechanisms of transcriptional regulation and its relationship to human disease.