The goal of the Section on Drosophila Gene Regulation is to understand the regulation of homeotic gene function in Drosophila. The homeotic genes specify segmental identities in Drosophila at both the embryonic and adult stages. They encode homeodomain-containing transcription factors that control cell fates by regulating the transcription of downstream target genes. The homeotic genes are expressed in precise spatial patterns that are crucial for the proper determination of segmental identities. Both loss of expression and ectopic expression in the wrong tissues lead to changes in segmental identities. These changes in identity provide a powerful assay to identify the trans-acting factors that regulate the homeotic genes and the cis-acting sequences through which they act. Both the homeotic genes and the trans-acting factors that regulate them are conserved between Drosophila and man. In addition to many conserved developmental genes, at least half of the disease and cancer-causing genes in man are conserved in Drosophila, making Drosophila a very important model system for the study of human development and disease. Genetic studies have identified the trithorax group of genes that are required for expression or function of the homeotic genes. Reduced function of the trithorax group genes mimics loss of function of the homeotic genes. Many trithorax group proteins are subunits of chromatin-remodeling or transcriptional coactivator complexes. The brahma, moira, and osa genes encode subunits of the Brahma chromatin-remodeling complex, which is conserved from yeast to human. To further understand the function of the Brahma complex, we have been characterizing mutations that interact with mutations in the Brahma complex. As part of these studies, we have recently isolated and characterized mutations in the Asf1 histone chaperone in collaboration with F. Karch (University of Geneva), J. Tamkun (University of California, Santa Cruz), and P. Verrijzer (Leiden University). We have shown that Asf1 is important for the structure of heterochromatin and that it interacts both functionally and physically with the Brahma chromatin-remodeling complex. In collaboration with J. Eissenberg and A. Shilatifard (St. Louis University) and A. Christensen (University of Nebraska), we have also isolated and characterized mutations in Su(Tpl), which encodes the Drosophila homolog of the ELL RNA polymerase II transcriptional elongation factor. We have shown that Su(Tpl) is required for the transcription of multiple developmental genes, including the Sex combs reduced homeotic gene. Su(Tpl) is within the first intron of the Mi-2 gene, which is required for transcriptional repression of the homeotic genes. In collaboration with W. McGinnis (University of California, San Diego), we have also isolated and characterized mutations in the Deaf-1 gene. The DEAF-1 protein was originally identified as a factor that bound to a cis-regulatory enhancer element from the Deformed homeotic gene. We have shown that Deaf-1 is essential for embryonic development.
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