Our lab is interested in the regulation of stress responses, metabolism, and aging. We study how transcriptional regulators adapt genome transcription in response to various types of stress or nutritional cues. These pathways are of great biomedical relevance. As an example, transcriptional activation of stress response programs helps cancers grow in hostile microenvironments featuring oxidative stress, starvation, and hypoxia; therefore, these pathways represent promising pharmacological targets to treat cancers.
Our research focuses on Mediator, a multi-protein complex that is evolutionarily conserved and vital for eukaryotic transcription, and its associated transcription factors such as Nuclear Hormone Receptors (NHRs). These regulators affect specific gene programs and can thus selectively implement biological processes. To study these important genes and proteins, we use the nematode worm Caenorhabditis elegans, the mouse, as well as cancer cell lines as genetically tractable models. See our publications page for details.
Our research focuses on Mediator, a multi-protein complex that is evolutionarily conserved and vital for eukaryotic transcription, and its associated transcription factors such as Nuclear Hormone Receptors (NHRs). These regulators affect specific gene programs and can thus selectively implement biological processes. To study these important genes and proteins, we use the nematode worm Caenorhabditis elegans, the mouse, as well as cancer cell lines as genetically tractable models. See our publications page for details.
Transcriptional control of stress responsesWe found that the C. elegans Mediator subunit MDT-15 is a central component in a cytoprotective network. MDT-15 protects worms from oxidative stress, hypoxia, starvation, toxins, heavy metals, and longevity. These responses are enabled by the physical interaction of MDT-15 with NHR-49, and with the redox regulator SKN-1/Nrf. We found a set of additional transcription factors and kinases that also act in this pathway. Current work is focused on delineating the action of these new stress response and longevity genes.
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Mediator in pancreas development & functionBecause MDT-15 regulates glucose and lipid metabolism as well as stress responses in worms, we have begun to study its ortholog MED15 in the mouse pancreas using genetic knockout models. We are interested in the pancreas and the insulin-secreting β-cells because they are stress-sensitive cells whose function and development involve complex transcriptional circuits.
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Mediator and stress resistance in cancer cellsOur work in C. elegans showed that MDT-15 promotes resistance to several stresses. We therefore hypothesize that its ortholog MED15 similarly promotes stress resistance in human cancer cells. We're using CRISPR genome editing to generate new MED15 null cancer cell lines an study the effect of this mutation on various properties of these cells. We hope that this will reveal whether targeting MED15 n cancers is a potential therapeutic strategy.
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A stress sensing kinase in C. elegansWe are interested in the stress sensing kinase efk-1/eEF2K. In collaboration with Dr. Poul Sorenson's lab, we showed inhibiting that this kinase is beneficial in worm models of Alzheimer's and Parkinson's disease. This appears to relate to a function of efk-1 in stress response. We're now using genetic and genomic approaches to study how efk-1 protects animals from stress.
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Techniques we use in the lab:
- Classical & advanced genetics (C. elegans: RNAi, CRISPR/Cas9, transgenesis, etc; mouse: Cre-Lox)
- Genomic techniques such as RNA-seq and ChIP-seq
- Functional genomic (RNAi) screens
- Gene expression analysis by qRT-PCR, GFP reporter analysis, immunofluorescence, immunoblot
- Protein-protein interaction analysis by yeast-two-hybrid and co-immunoprecipitation
- Advanced compound and confocal fluorescence microscopy
- A wide range of behavioural, metabolic, and survival assays
- FACS to purify cell populations of interest from worms or mouse tissues
Current collaborators (for past collaborators, please see our publications)
- Poul Sorenson, BC Cancer Agency
- Francis Lynn, BCCHR Diabetes
- Bruce Verchere, BCCHR Diabetes
- Frédéric Picard, University Laval
- Dana Miller, University of Washington, USA
- Javier Irazoqui, University of Massachusetts Medical School, USA
- Amy Walker, University of Massachusetts Medical School, USA
- Seung-Jae Lee, Pohang University of Science and Technology, Korea
- Jenny Watts, Washington State University, USA