Stefan Taubert, PhD – Department of Medical Genetics, University of British Columbia — CSB Seminar

CSB Departmental Seminar

Friday, April 10th @ 11:00 am

SPEAKER: Stefan Taubert, PhD – Department of Medical Genetics, University of British Columbia

TITLE: Transcriptional regulation of stress responses in C. elegans and human cancer cells.

ABSTRACT:

The accumulation of molecular and cellular damage is a key driver of aging and age-related diseases such as cancers, type 2 diabetes, and neurodegenerative disorders. Normally, damage accumulation is mitigated by stress response networks. These networks engage evolutionarily conserved transcription factors, which rewire gene expression to promote homeostasis of cells, tissues, and organisms. To identify and study conserved longevity and stress response networks, we use the nematode C. elegans and cancer cell lines. We study a critical and evolutionarily conserved transcription coregulator, the Mediator complex, focusing on Mediator subunit 15 (MED15/MDT-15). Previous work showed that loss of C. elegans mdt-15 or of its key partner, nuclear hormone receptor nhr-49, impairs longevity- and stress-induced gene expression, shortens life span, and sensitizes animals to stressors such as pro-oxidants, hypoxia, or starvation; vice versa, mdt-15 or nhr-49 gain of function increases life span and stress resistance. Downstream, MDT-15 and NHR-49 regulate fatty acid metabolism, autophagy, and other processes to promote longevity and resilience. However, how gene programs are tailor made to each stress and how MDT-15 and/or NHR-49 are activated in longevity or stress contexts remains unclear. To study these problems, we are performing genetic screens for new pathway components and proteomic analysis of NHR-49 using IP-MS and BioID protein proximity labelling in various conditions. Collectively, our studies suggest emerging roles for several kinases and for post-transcriptional mRNA processing and export in MDT-15–NHR-49 stress resilience. Finally, to test if this regulatory network has evolutionarily conserved roles in stress resilience, we deleted MED15 in human A549 lung cancer cells. Transcriptome and functional analysis suggest that MED15 promotes antioxidant and pro-inflammatory signalling, with critical roles in regulating chemokine/cytokine-dependent interactions of cancer cells with immune cells. Collectively, our studies suggest that MED15 and its associated transcription factors control stress resilience across species and that these circuits are critical in the context of at least one age-associated diseases, cancer.

HOST: Arneet Saltzman

LOCATION: Cell and Systems Biology, 25 Harbord Street, Suite 432

LIVESTREAM LINK: https://csb.utoronto.ca/live-stream/