Substantial progress has been achieved, to date, in determining the parameters and features responsible for the activity of individual genes. But relatively little is known of the mechanisms which coordinate and integrate multiple gene function. We have been studying the phenomenon of dosage compensation in Drosophila as model system to coordinate gene regulation. Dosage compensation results in the equalization of X-linked gene products in males and females. It involves the mudulation of the transcriptional level of a large fraction of the genome (the vast majority of genes on the X chromosome are compensated). It also represents a regulatory mechanism which is superimposed on the various developmental programs which regulate the time and tissue distribution of individual X-linked genes. Our goal is to understand the regulatory mechanism(s) of compensation at the molecular level. To this end we will study the signals which modulate the synthesis of the regulatory factors and the means by which they achieve their function. We will identify the DNA sequences on the X chromosome which respond to the regulatory factors to mediate dosage compensation. To achieve these goals, we will continue to use formal genetic tools to identify genomic components and establish phenotypic parameters. We will also greatly expand the molecular investigations which we had begun by entering into an extensive collaboration with Jerry Manning, UC-Irvine. The sex related phenomena on which we are focusing have been extensively studied in humans. Although significant differences exist, certain fundamental similarites insure that our work has considerable relevance to the understanding of human regulatory processes.
