• Taubert, Stefan

    Titles

    Investigator, BC Children's Hospital
    Scientist, Centre for Molecular Medicine and Therapeutics at CFRI
    Associate Professor, Department of Medical Genetics, University of British Columbia

    Degrees / Designations
    PhD
    Primary Area of Research
    Healthy Starts
    Secondary Area(s) of Research
    Phone
    604-875-3860
    Fax
    604-875-3819
    Lab Phone
    Assistant
    Dora Pak
    Assistant Phone
    604-875-2345 ext, 5273
    Mailing Address
    Centre for Molecular Medicine and Therapeutics
    Room 3018, 950 West 28th Avenue
    Vancouver, BC V5Z 4H4
    Affiliate Websites
    www.cmmt.ubc.ca/research/investigators/taubert/lab
    Research Areas
    • Gene expression/transcription
    • Regulatory networks
    • Genetic interactions
    • Lipid biology
    • Stress response (fasting, toxins, heavy metals, oxidative stress)
    • Metabolic diseases (obesity, diabetes)
    • Nuclear Hormone Receptors
    Summary
    In all organisms, DNA is the matter of inheritance. As such, DNA provides the blueprint to build and operate each individual organism. Decoding the information contained in the DNA is thus a key process, termed ‘transcription’. Transcription needs to happen at the right time and in the right place, and deregulated transcription causes diseases such as cancers, diabetes, and developmental abnormalities. But how does a creature transcribe the specific DNA programs to develop a normal, functioning organ, or to adapt its life-style to a specific external influence?
     

    My lab studies the so-called ‘Mediator’, a molecular machine that is required for transcription: without it, the information contained in DNA cannot be properly decoded. Intriguingly, several Mediator subunits are mutated in human diseases, including certain cancers and neurodevelopmental disorders, but how and why the Mediator mutations cause disease remains poorly understood.

    Our mission is to define why and how Mediator function assures normal development, prevents sickness, and promotes healthy aging. We use the worm Caenorhabditis elegans and the house mouse as experimental animal models, because they share certain aspects of human biology, and because we can control their genetics. With this approach we dissect how individual Mediator subunits regulate lipid metabolism and fat storage, detoxification programs, organ development and differentiation pathways, and aging. By providing new insights into how DNA is transcribed, our investigations may lead to new diagnostics and/or therapeutics that can help cure human diseases.


    Current Projects
    The Mediator is universally required for Polymerase II-dependent transcription, but some Mediator subunits affect specific gene sets and selectively implement biological programs. This is exemplified by our research on MDT-15 and CDK-8, two subunits of the C. elegans Mediator complex. MDT-15 integrates the transcription of genes involved in lipid biology and in the response to nutrition-associated stresses (fasting, heavy metals, xenobiotic toxins, and oxidative stress). Thus, we hypothesize that MDT-15 is a key component in a conserved metabolic regulatory network, and that its orthologue MED15 may be involved in human metabolic conditions such as obesity and diabetes. CDK-8 is the kinase of the Mediator complex, and it plays important roles during C. elegans development and differentiation. Intriguingly, its human ortholog CDK8 is an oncogene, but its normal function in development and physiology remains poorly understood. Our current projects address various elements of MDT-15 and CDK-8 function in C. elegans or mice.

     CURRENT PROJECTS

    1. MDT-15 driven metabolic homeostasis: MDT-15 is required to maintain metabolic homeostasis in C. elegans, but how altered lipid balance affects organelle, cellular, and organismal function remains poorly understood. Our experiments aim to delineate the consequence of lipid imbalances in worms lacking mdt-15, and how lipid metabolism and oxidative stress responses impinge on organismal health and aging.

    2. MDT-15 interacting factors and molecular determinants: MDT-15 is the centre of a regulatory network that includes many Nuclear Hormone Receptors (NHRs). However, which, if any, part of MDT-15’s function these NHRs perform is unclear; moreover, we do not yet understand the molecular details of these interactions. Using advanced genetic, genomic, and biochemical methods, we are defining the individual roles of this network’s components.

    3. Conservation of MED15 function in mammals: Given the metabolic regulatory role of MDT-15 in C. elegans, we are testing whether MED15, its mammalian homologue, performs similar functions. Using candidate and unbiased genomic approaches we aim to identify MED15's transcriptional targets and biological functions in cultured cells. Additionally, we have generated tissue-specific MED15 loss-of-function and we are now investigating their metabolic and developmental phenotypes.

    4. Developmental regulation by CDK-8: In humans, CDK-8 is an oncogene but its role in normal development remains poorly understood. Benefitting from viable null or hypomorph mutations we have begun to dissect the role of CDK-8 and its associated module in C. elegans, and have found important roles in development and differentiation. In these contexts, CDK-8 engages several conserved signaling pathways, and our current research uses genetics and genomics to dissect the underlying molecular mechanism.

    Selected Publications

    Grants JM, Goh GY, Taubert S. The Mediator complex of Caenorhabditis elegans: insights into the developmental and physiological roles of a conserved transcriptional coregulator. Review. Nucleic Acids Res. 43(4):2442-53. (2015) PMID 25634893

    Hou NS, Gutschmidt A, Choi DY, Pather K, Shi X, Watts JL, Hoppe T, Taubert S. Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo. Proc. Natl. Acad. Sci. U.S.A. 111(22):E2271-80. (2014) PMID 24843123

    Goh GY, Martelli KL, Parhar KS, Kwong AW, Wong MA, Mah A, Hou NS, Taubert S. The conserved Mediator subunit MDT-15 is required for oxidative stress responses in Caenorhabditis elegans. Aging Cell 13(1):70-9. (2014) PMID 23957350

    Grants
    Honours & Awards
    Canada Research Chair Tier 2 - renewal (2014-2019)

    NSERC Discovery Grant (2013-2018)
    CIHR Catalyst Grant (2010-2011)
    CIHR Operating Grant (2009-2014)

    Research Group Members
    Jennifer Grants, PhD student
    Grace Goh, PhD student
    Kayoung Lee, MSc student
    Robyn Cullen, Research Assistant 
    Arshia Beigi, Undergraduate Research Assistant 
    James Shih, Undergraduate Research Assistant 
    Amy Poon, Volunteer
    Frederic Picard, Visiting Professor (U Laval)
    Dora Pak, Research Coordinator