We are interested in understanding the deregulation of epigenetic and transcriptional pathways in human disease and in finding small molecules with therapeutic potential to normalize these gene expression patterns. Our current efforts are focused on five main exciting projects:
1. Identifying and characterizing new epigenetic modulators with potential as therapeutic drugs and as research tools to discover new biology.
This is our most advanced project. Our top compound, JIB-04, is now being used worldwide in epigenetic research and is sold by over ten companies. We discovered it and characterized it as a Jumonji histone demethylase inhibitor. These enzymes are overexpressed in cancer. Inhibiting them kills cancer specifically, and sensitizes malignant tumors resistant to standard therapeutics.
2. Profiling human tumors to define novel molecular epigenetic targets
Using clinically annotated patient samples, we have discovered an ‘epigenetic signature’ with prognostic value that outperforms all the current signatures in the literature. We are now functionally validating this signature to evaluate its clinical application.
3. Evaluating the interplay between the immune system and epigenetic regulation
With the advent and high promise of immune therapy such as checkpoint blockade, we are pursuing epigenetic strategies to sensitize resistant cancers to immune interventions.
4. Defining the role of Jumonji enzymes in normal physiology and in infectious disease
Development, differentiation and adaptation to environmental cues, including pathogenic infections, require plasticity in transcriptional programs. We are characterizing the key roles Jumonji histone demethylases play in reprogramming gene expression patterns in normal physiology and in infectious disease including malaria and HIV.
5. Define and modulate the function of the three putative Jumonji histone lysine demethylases in the malaria parasite, Plasmodium falciparum.
Histone modifications play an essential role regulating gene transcription in Plasmodium falciparum throughout its complex life cycle. We focus on histone methylation in the intra-erythrocytic stage of the life cycle. Tri-methyl histone marks are required for both gene activation and silencing in the malaria parasite. Jumonji histone lysine demethylases are the only enzymes enzymatically capable of demethylating these tri-methyl marks in order to silence actively transcribed genes or activate silenced genes. P. falciparum encodes three putative genes encoding Jumonji domains. We are using genetic, biochemical, and pharmacological approaches to define the essentiality and function of these enzymes regulating transcription in malaria parasite.
Come by and find out more about our research and the open grad student positions!