The long term goal of this research is to understand the molecular mechanisms underlying stable long term maintenance of the patterns of homeotic gene expression during Drosophila development. The Trithorax Group (trxG) and Polycomb Group (PcG) proteins are directly involved in this process and are respectively required for the maintenance of active and inactive transcriptional states established in the early embryos. Evidence increasingly suggests that they function by promoting stable changes in local chromatin structure. This proposal is to investigate the role of the Trithorax protein (TRX) and Polycomb Group protein Extra sex combs (ESC). TRX and ESC have been highly conserved in diverse phyla, suggesting that their fundamental functions are ancient and highly conserved. Understanding how they function will provide new insights into the mechanisms of transcriptional regulation as well as the mechanisms underlying development of normal body plans in animals. We have shown that the natural response elements for both TRX and PcG proteins are intimately associated on the same DNA elements, including promoters, and that at least one PcG protein binds directly to TRX, suggesting that TRX and PcG proteins may directly modulate each other's activity. We will further characterize TRX and ESC response elements in the Ubx gene. We will investigate how TRX and ESC exert their positive and negative regulatory effects by tethering them near promoters and enhancers to see if they possess intrinsic transcriptional activation or repression activity. We will continue to investigate the function of a number of other proteins that are physically associated with TRX and ESC and initiate genetic investigations of a number of newly identified proteins associated with both. We will determine how they function in concert with TRX and ESC to promote maintenance of transcriptional states. Mutations in the human TRX homolog MLL are associated with acute leukemias, while several human PcG proteins are implicated in immune system dysfunction and tumorigenesis. Understanding the fundamental mechanism of TRX and ESC action should also provide insights into the role of their human homologs in disease.
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