Fly Lab
One fusion partner of MLL in acute myelogenous leukemia (AML) is the ELL protein. We show that human ELL functions as a transcription elongation factor. We have identified the Drosophila homolog of ELL and demonstrate it to be essential for development. Drosophila ELL associates with elongating RNA polymerase II in vivo on chromosomes and is a regulator of the Notch signaling pathway. This has suggested to us that human ELL might also participate in the same process.
In light of the identificaton of three ELL-related proteins in human, we show that they all share a conserved C- terminal domain, which is not required for the transcription elongation properties of the ELLs. We show that in Drosophila, ELL's C-terminal domain is essential for development and the equivalent region of human ELL is critical for hematopoietic immortalization. Therefore, defining the molecular role for ELL's C-terminal domain in Drosophila development is a major focus of our laboratory.
We have also taken advantage of RNAi technology in Drosophila to reduce the levels of the factors required for proper histone modifications to define their role in a living organism. We show that the components of the Rad6/Bre1, the Paf1 complex, and other factors are required for histone methylation. Furthermore, we have recently identified that the trithorax group gene in Drosophila, called little imaginal discs, encodes a histone trimethyl H3K4 demethylase. We are planning to follow through with our Drosophila studies to better define the molecular machinery involved in histone methylation and how the misregulation of their activities results in cellular immortalization.