Role of the epigenetic reader LEDGF/p75 in health and disease

The transcriptional co-activator LEDGF/p75 was originally identified in our lab as important host factor of HIV integration. Since, this protein has been recognized as a molecular tether that juxtaposes various cargo proteins to epigenetic marks on nucleosomes associated with active transcription. The N-terminal PWWP domain recognizes H3K36me2/3. Besides its role in HIV replication, the protein plays a role in the pathogenesis of Mixed Lineage Leukemia, both diseases with a high medical need.In this project we will investigate the cell biology of LEDGF/p75, more specifically we will study how it acts as an epigenetic reader to activate transcription. In WP1 we will study the biophysical properties of the protein and its respective complexes with HIV integrase, and MLL fusion proteins a in vitro and in cell culture. We will also study the interactions with MED1 and BRD4. In a second work package we will study the role of (super)enhancers and MLL in HIV transcription (WP2). In WP3 we will investigate the role of LEDGF/p75 and its paralogue HRP2 in cell survival. In a last work package (WP4) we will embark in fragment-based drug discovery to find inhibitors of the PWWP-chromatin interaction.

Keywords:HIV virology, epigenetics, HIV cure, LEDGF/p75

Disciplines:Virology, Epigenetics