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 down-stream 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.

Transcriptional Activators of Homeotic Genes
Kennison, Green, Cooper in collaboration with M. Vázquez, Cuernavaca, Mexico
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 of genes mimics loss of function of the homeotic genes. Many of the trithorax group of genes have been shown to be required for the maintenance of transcription of the homeotic genes during development. Our laboratory has identified at least two dozen trithorax group genes, most of which were previously unknown. Two of the genes (skuld and kohtalo) encode subunits of the mediator coactivator complex. This complex is highly conserved between Drosophila and man, but only about a third of the subunits are conserved between yeast and man. Three other genes (brahma, moira, and osa) encode subunits of a chromatin-remodeling complex conserved from yeast to man. We have used genetic screens to identify a number of other genes that interact with the brahma complex in regulating two different homeotic genes targets. The brahma-interacting genes tonalli and taranis encode zinc-finger and antifreeze proteins, respectively. The trithorax group gene kismet encodes a brahma-related protein that is a subunit of a third protein complex. The kismet protein is also conserved between Drosophila and man and appears to be a subunit of a chromatin-remodeling complex that is not found in yeast. The verthandi gene, which is also required for the transcriptional regulation of homeotic genes, has been mapped to a heterochromatic chromosomal region that is not on the current molecular maps of the Drosophila genome.

Transcriptional Repressors of Homeotic Genes
Kennison in collaboration with J. Müller, Tübingen, Germany and A. Birve, Umea, Sweden
The initial domains of homeotic gene repression are set the by the segmentation proteins, which also divide the embryo into segments. Maintenance of repression requires the proteins encoded by the Polycomb group genes. The switch from the initiation to the maintenance of repression involves the recruitment of a chromatin-remodeling complex that includes the brahma- and kismet-related protein Mi-2 and a histone deacetylase subunit. Maintenance also requires the Polycomb complex, which likewise has a histone deacetylase subunit. We have identified and characterized a new Polycomb group gene, Su(z)12,that encodes a zinc-finger protein and is required both maternally and zygotically for the maintenance of homeotic gene repression. In collaboration with the Section on Gene Expression, we have also begun a large genetic screen for new Polycomb group genes.

Cis-Acting Sequences Required for Homeotic Gene Repression
Kennison, Cooper
Assays in transgenes in Drosophila have previously identified cis-acting repressor elements from the homeotic genes. These cis-acting repressor elements are called PREs (Polycomb group response elements). We have used a large number of existing chromosomal rearrangements in the Sex combs reduced homeotic gene to investigate the cis-acting elements required for transcriptional repression. These chromosomal rearrangements identify two genetic elements about 70 kb apart in the Sex combs reduced gene that must be in cis to maintain proper repression. When not physically linked to each other, the genetic elements interact with elements on the homologous chromosome and cause derepression of its wild-type Sex combs reduced gene. We are currently characterizing a mutant chromosome that appears to carry a novel insertion of one of these elements.