LSD1 IMPACT · Dissecting the interaction network of the histone demethylase LSD1 in vivo

Each cell within an organism contains the same genetic information, however, only a specific subset of genes is transcribed in a given cell at a given time. This cell/stage specific transcription is controlled by the coordinated action of signaling pathways, chromatin associated proteins and transcription factors. Defects in chromatin organization and gene expression due to aberrant activity of chromatin modifying enzymes can contribute to diseases such as cancer. Since its discovery, the histone demethylase LSD1 has emerged as a key chromatin regulator. Several studies have implicated LSD1 in tumorigenesis and there is a growing interest in its use as a drug target. However, we still have a limited knowledge of LSD1 pathway-specific functions and a genome-wide study of its role in a whole organism is lacking.My strategy is to use an animal model system, Drosophila melanogaster, to dissect LSD1 function in vivo. My work has shown that mutation of LSD1 Drosophila ortholog, dLsd1 impacts specific developmental processes. Taking advantage of the tools available in Drosophila, I discovered a surprising antagonism between the histone H3K4 demethylases dLsd1 and Lid at chromatin boundaries and an involvement of dLsd1 in the Notch signaling, which we found to be conserved in mammals. To identify novel pathways involving dLsd1 in vivo, my lab is carrying out a genome-wide RNAi screen in Drosophila. We plan to study how dLsd1 and key candidates discovered in the screen control gene transcription and chromatin homeostasis in specific developmental contexts. We then plan to take a few new key interactions and to test whether this newly acquired information is conserved in mammals and can be exploited to target tumor cells. The goal is to provide insights into the LSD1 network of interactions, which will be instrumental for understanding the mechanisms that control chromatin structure and gene transcription and how their deregulations leads to diseases such as cancer.""