Transcriptional regulation in Drosophila: the post-genome challenge

Drosophila melanogaster has long been at the forefront of studies of transcriptional regulation in animals. Many fundamental ideas--such as cis control elements that act over long distances, the regulation of development by hierarchical cascades of transcription factors, dosage compensation, and position effect variegation--originated from studies of the fruit fly. The recent completion of the euchromatic DNA sequence of Drosophila is another breakthrough. The sequence data highlight important unanswered questions. For example, only one-fifth of the 124 Mb of Drosophila euchromatic DNA codes for protein. The function of the remaining 100 Mb of mostly unique DNA is largely unknown. Some proportion of this non-reading frame DNA must encode the functional recognition sites targeted by the approximately 700 sequence-specific DNA binding proteins that regulate transcription in Drosophila, but what proportion? Most or very little? Promoter sequences by definition contain all of the cis information that specifies how gene transcription is regulated. However, it has been difficult to decipher this information and predict the patterns of RNA expression. How do we break this "transcriptional code"? Mechanistic studies, using simple model promoters, indicate that transcription is controlled by the coordinate action of sequence-specific DNA binding proteins interacting with the general transcriptional machinery via intermediary adapters and chromatin remodeling activities. How can we integrate this biochemical information with data from genome-wide studies to describe the generation of highly complex patterns of transcription? Here, we discuss recent studies that may point the way ahead. We also highlight difficulties that the field faces in dissecting transcriptional control in the post-genome era.