Stefan Taubert

Associate Professor

Research Interests

Aging
beta cells
C. elegans
Diabetes
Gene Regulation and Expression
Gene regulation
Genetics of Aging
genomics
Hypoxia
Metabolism
Molecular Genetics
Mouse
stress
Stress and Cancer
Stress responses
Toxin and Toxicant Metabolism
Transcription

Relevant Thesis-Based Degree Programs

Research Options

I am available and interested in collaborations (e.g. clusters, grants).
I am interested in and conduct interdisciplinary research.
I am interested in working with undergraduate students on research projects.
 
 

Biography

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.

Research Methodology

C. elegans (worm)
Mouse models (tissue-specific KOs)
cell culture
molecular genetics
Functional genetics
Transcriptomics (RNA-seq)
Protein protein interactions
Functional genomics

Recruitment

Master's students
Doctoral students
Postdoctoral Fellows
2024

We study how cells, tissues, and organisms adapt to stresses (hypoxia, oxidative stress, starvation) and how their function is compromised during aging. We investigate these processes and cellular responses because they contribute to or even cause human pathologies, such as cancers, diabetes, and neurodegenerative disorders. 

We are especially interested in gene regulation by the Mediator complex, an essential eukaryotic transcriptional regulator that is mutated or deregulated in human diseases (cancers, developmental disorders, etc.), and by Nuclear Hormone Receptors, as well as other signalling molecules these factors interac with. 

We use multiple model systems: The nematode worm C. elegans, the mouse (tissue-specific genetic KO models, especially in the pancreas), and cultured human cancer cell lines. We employ classic and state-of-the-art genetic, genomic, and molecular approaches (forward and reverse genetic screens, RNA-seq, CRISPR-Cas9 genome editing, RNA interference, yeast-two-hybrid, etc.). Projects revolve around characterizing how individual Mediator subunits,  transcription factors, and kinases control stress adaptation and aging, and to identify which cellular signalling pathways these factors interact with to regulate metabolism and stress adaptation. 
For more information, see https://taubertlab.weebly.com

Ideal applicants have excellent grades, a proven track recrod and experiense in research, and an abiltiy to work in a team and independently.

Applicants interested in a position should email Stefan their CV, transcripts (grad & undergrads only), statement of research interest, & contact info for references. 

​- Interested and highly qualified graduate students (click for guidelines and application procedures for the MEDG and CELL graduate programs) and postdocs should contact Stefan directly
- Potential undergraduate students (coop students, directed studies students, summer students, work-learn students, volunteers) should also contact Stefan

I support public scholarship, e.g. through the Public Scholars Initiative, and am available to supervise students and Postdocs interested in collaborating with external partners as part of their research.
I support experiential learning experiences, such as internships and work placements, for my graduate students and Postdocs.
I am interested in hiring Co-op students for research placements.
I am interested in supervising students to conduct interdisciplinary research.

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ADVICE AND INSIGHTS FROM UBC FACULTY ON REACHING OUT TO SUPERVISORS

These videos contain some general advice from faculty across UBC on finding and reaching out to a potential thesis supervisor.

Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

The Caenorhabditis elegans nuclear hormone receptor NHR-49 functions in stress response pathway regulation (2022)

The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.

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Investigating the role of transcriptional coactivator MED15 in beta cell maturation (2020)

The Mediator complex, a coregulator required for RNA pol II activity, interacts with specific transcription factors through its distinct subunits. These interactions promote the expression of defined gene sets both during development and for tissue homeostasis. Transcriptional regulatory networks are critical for the development and function of pancreatic β-cells. To date, few studies examining how transcription factors interact with co-activators, such a Mediator, have been performed in the pancreas. Tail module subunit MED15 is highly expressed in nascent β-cells and required for lipid metabolism, various stress responses, and TGF-β signalling, all of which are important for β-cell function. As such, we hypothesized that MED15 plays a role in β-cells. We found MED15 to be expressed during mouse pancreatogenesis and in mature β-cells. Expression of MED15 was impaired in human T2D islets suggesting it is important for mature β-cell function. After generating a β-cell specific knockout mouse (IM15KO), we observed defects in maturation as assessed by loss of β-cell maturation markers UCN3, MAFA, and GLUT2. In agreement with reduced GLUT2 expression, IM15KO cells had impaired glucose uptake and reduced glucose-stimulated insulin secretion, the hallmark process of β-cell maturation. ChIP-seq analysis determined that MED15 is bound to key GSIS related genes and Co-IP found transcription factors NEUROD1 and NKX6-1 to bind MED15. As the pancreas contains among the highest levels of Zn²⁺ in the body, we also found a role for MED15 in heavy metal stress response. Through this thesis, I provide evidence of the importance of Mediator in β-cell maturation and demonstrate an additional layer of control that modulates transcription factor function. A greater understanding of how Mediator and MED15 regulate β-cell maturation could help refine the generation of cell-based therapies for diabetes.

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Transcriptional regulation of oxidative stress responses in the nematode Caenorhabditis elegans (2017)

Reactive oxygen species are chemically reactive molecules that are crucial for many cellular functions, but their buildup can cause toxic damage, otherwise known as oxidative stress. Oxidative stress is thought to cause or exacerbate many diseases. To defend themselves against oxidative stress, cells mount sophisticated defenses to remove ROS and repair damage caused by ROS. In particular, sequence-specific DNA binding transcription factors induce the expression of cytoprotective enzymes upon stress. In the model organism Caenorhabditis elegans, the transcription factor SKN-1 is considered a “master regulator” that is required to activate many cytoprotective and antioxidant genes, and is critical for resistance to oxidative stress. However, little is known about whether and how SKN-1 interacts with transcriptional coregulators, essential factors that help specify transcriptional responses. Moreover, although evidence exists for SKN-1 independent oxidative stress responses, the responsible transcription factors are unknown. In this thesis, I identified a subunit of the Mediator transcriptional coregulator complex, MDT-15, as a coregulator for skn-1-dependent oxidative stress responses. This role is independent of a previously identified role for MDT-15 in lipid metabolism. Additionally, I found that mdt-15 is also required for skn-1-independent oxidative stress responses. Using a candidate reverse genetic screen, I identified an MDT-15-interacting transcription factor, the nuclear hormone receptor NHR-49, as a regulator of a SKN-1-independent oxidative stress response. Interestingly, some NHR-49-dependent stress response genes were also upregulated in fasting and in long-lived germline-less mutants, indicating a shared response in all three conditions. In summary, this thesis provides the first description of MDT-15 as a coregulator of SKN-1 and identifies a new role for NHR-49 in the oxidative stress response. SKN-1, NHR-49, and MDT-15 are all conserved in humans, and the human orthologs of SKN-1 and NHR-49 also interact with the Mediator complex. Thus, my work offers therapeutic implications for diseases in which oxidative stress plays a role, such as cancer, metabolic diseases, and other age-related diseases.

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Roles of Mediator Subunit CDK-8 in Developmental and Physiological Responses in Caenorhabditis Elegans (2016)

The Mediator complex is a conserved coregulator of RNA polymerase II transcription. Whereas some Mediator subunits are universally essential for transcription, others regulate specialized gene programs by interacting with sequence-specific transcription factors (TFs). Mediator’s Cyclin dependent kinase 8 (CDK8) kinase module (CKM) consists of four subunits (CDK8, Cyclin C, MED12, MED13) and regulates transcription downstream of multiple cell signaling pathways. In addition, the CKM regulates other Mediator subunits, as CDK8-mediated phosphorylation promotes Mediator subunit turnover, at least in yeast. CKM subunits have been identified as human oncogenes or tumor suppressors, indicating that the CKM can modulate transcription in tumorigenesis. However, the roles of the CKM in animal development and physiology are less well understood, as its target TFs often remain undefined. Furthermore, whether the CKM regulates the activity of other Mediator subunits in metazoans remains unknown. In this dissertation, I investigated CKM interactions with TFs and other Mediator subunits in Caenorhabditis elegans development and physiology. Gene expression profiling of C. elegans cdk-8 mutants implicated CDK-8 in regulation of epidermal growth factor receptor (EGFR)-Ras-extracellular signal-regulated kinase (ERK)-driven transcription and cadmium-responsive transcription. I showed that the CKM inhibits ectopic vulval cell fates downstream of the EGFR-Ras-ERK pathway, dependent on CDK-8 kinase activity. Mechanistically, the CKM inhibits EGFR-Ras-ERK pathway output by promoting transcriptional repression by the LIN-1/Elk1 TF, and by inhibiting transcriptional activation by the Mediator subunit MDT-15. Furthermore, cdk-8 is required for post-transcriptional regulation of MDT-15. Therefore, the CKM restrains EGFR-Ras-ERK signaling in C. elegans development by regulating TF and Mediator activity. I also studied cdk-8 in the cadmium response. I showed that cdk-8 is required for cadmium-inducible transcription and organismal cadmium resistance. Dissecting a modular cadmium-responsive promoter, cdr-1, I showed that cdk-8 may cooperate with other factors known to regulate cadmium-responsive transcription: mdt-15, GATA-family TF elt-2 and GATA elements, and a high zinc-activated (HZA) element. I speculate that CDK-8 promotes cadmium-inducible transcription by activating MDT-15, ELT-2, or an HZA-binding TF. In sum, cdk-8 cooperates with distinct TFs, and can oppose or cooperate with the Mediator subunit mdt-15, to regulate EGFR-Ras-ERK-inducible vs. cadmium-inducible transcription.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Characterization of the transcriptomic response to acute starvation in the C. elegans hypodermis (2023)

The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.

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Identification of metabolic alterations that activate the unfolded protein response of the endoplasmic reticulum in C. elegans (2021)

Endoplasmic reticulum (ER) stress due to protein misfolding or membrane lipidimbalance is observed in many diseases. ER homeostasis can be restored by activation of theunfolded protein response (UPR-ER), which, in higher eukaryotes, consists of three parallelbranches: The Inositol-Requiring-Enzyme 1 (IRE-1) branch, the protein kinase RNA-like ERkinase (PEK-1) branch, and the Activating Transcription Factor 6 (ATF-6) branch. These sensorsactivate downstream effectors to restore cellular homeostasis. However, we lack a global view ofgenetic perturbations that activate the UPR-ER in metazoans. To identify\metabolic pathwaysthat affect ER homeostasis, I used RNA interference (RNAi) to inactivate 1247 metabolic genesin Caenorhabditis elegans using an IRE-1 branch specific transcriptional reporter, hsp-4p::gfp.After screening and validation, I obtained 34 high-confidence hits that also activate the PEK-1branch. Next, using a strain lacking the key IRE-1 pathway effector XBP-1 (xbp-1; hsp-4p::gfp),I showed that these gene inactivations induce canonical IRE-1 signaling. Moreover, dietarycholine supplementation, which suppresses UPR-ER in worms defective for phosphatidylcholine(PC) synthesis pathway, partially suppresses UPR-ER activation in 3 of the 34 hits, suggestingthat most hits do not activate the UPR-ER via defective PC synthesis. Finally, I performedfollow-up studies on two of the 34 hits, the primases pri-1 and pri-2, whose inactivation causesDNA damage due to replication fork stalling. These two RNAi clones were selected becauseboth activate hsp-4p::gfp in C. elegans embryos in a partially ire-1-, xbp-1-independent manner.I observed that pri-1 and pri-2 RNAi specifically induce the UPR-ER, but not themechanistically distinct cytosolic or mitochondrial UPRs. This suggests that pri-1 and pri-2RNAi do not cause global protein misfolding. Interestingly, genomic instability caused by loss of DNA repair pathways did not activate the UPR-ER, suggesting that replication stress specificallyactivates the UPR-ER in the embryo. In sum, by identifying new genes that affect UPR-ERhomeostasis in C. elegans, my project provides new insights into mechanisms of UPR-ERregulation. Furthermore, as many genes identified here have human homologues, my data mayprovide a starting point for the discovery of novel drug targets for human diseases featuring ERdysfunction.

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A regulatory mechanism of zinc homeostasis involving the mediator subunit MDT-15 and the transcription factor HIZR-1 (2018)

Zinc is a metal that is essential for cell function as it plays important catalytic and structural roles in many proteins; however, excess zinc causes cell stress. Cadmium has similar chemical properties as zinc but is toxic and not required in biological systems. To maintain homeostasis, the levels of zinc detoxification genes are modulated through transcriptional regulation, which allows organisms to adapt to environmental changes. The key players in transcriptional regulation are Transcription Factors (TF), regulatory DNA elements, and coregulators such as the Mediator complex. Mediator subunit MDT-15 is required for the regulation of stress response genes in Caenorhabditis elegans, including zinc responsive genes. However, MDT-15’s physiological role and its regulatory partners in zinc homeostasis and cadmium stress response remain unknown. In this study, I investigated which TFs collaborate with MDT-15 to regulate zinc homeostasis and cadmium stress response genes, and I also examined its physiological role in zinc homeostasis. I used a fusion of the promoter of the zinc and cadmium responsive gene cdr-1 to Green Fluorescent Protein (GFP) and real-time PCR analysis as sensitive readouts to study metal response mechanisms. I found that cdr-1 induction by zinc and cadmium depends on Mediator subunits mdt-15 and cdk-8, and the TFs high zinc activated nuclear receptor-1 (hizr-1) and elt-2. Using genetic interaction studies, I found that HIZR-1 and MDT-15 function is codependent, and showed, using the yeast-two-hybrid system, that the two proteins interact physically. Interestingly, this physical association was enhanced by micromolar zinc and cadmium. To assess zinc storage, I studied the gut granules of C. elegans, which store and replenish zinc to maintain homeostasis, and found storage defects in mdt-15 and hizr-1 mutants. Lastly, I explored the regulatory conservation of this regulatory mechanism. The Insulin Secretory Granules in pancreatic β-cells require appropriate amounts of zinc to crystallize insulin. Using mice lacking the mdt-15 ortholog Med15 in the β-cells, I found that Med15 is required to express Slc30a8, the ortholog of the mdt-15-regulated zinc transporter cdf-2. Collectively, my data show that mdt-15 and hizr-1 cooperate to regulate metal detoxification genes and zinc storage, through a mechanism that possibly is conserved.

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Functional characterization of gene regulation by nhr-49 (2016)

Nuclear hormone receptors (NHRs) are transcription factors that regulate a wide variety of developmental and physiological processes. NHRs are targets of numerous drugs. However, due to limited knowledge on NHR specificity, many such drugs activate multiple biological pathways downstream of NHRs, leading to undesired side effects. To study NHR specificity in vivo, I used the model organism Caenorhabditis elegans. One C. elegans NHR is NHR-49, which regulates various aspects of lipid metabolism. Specifically, it activates genes involved in fatty acid desaturation and fatty acid β-oxidation by binding to a subunit of the Mediator multiprotein complex, MDT-15. Vice versa, NHR-49 represses genes involved in sphingolipid breakdown by heterodimerizing with another C. elegans NHR, NHR-66. Recently, three point mutations in nhr-49 were identified that promote fatty acid desaturation, but whether these alleles act specifically in this pathway or also affect other nhr-49 regulated processes is not clear. To test whether the mutated residues are linked to specific biological functions, I studied how they affect gene expression and protein-protein interactions by real time quantitative PCR and Yeast 2 Hybrid assays. I found that the three point mutations have different effects on nhr-49 dependent metabolic processes. While all three alleles broadly promoted nhr-49 dependent activation, only one allele affected nhr-49 dependent repression. This shows that the mutations and the corresponding amino acid residues have some association with specific nhr-49 dependent biological processes.

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In vivo activation of the endoplasmic reticulum unfolded protein response without disturbed proteostatis (2014)

The Mediator is a conserved transcriptional co-factor complex required for eukaryotic gene expression. In C. elegans, the Mediator subunit mdt-15 is essential for the expression of genes involved in fatty acid metabolism and ingestion-associated stress response. mdt-15 loss-of-function causes defects in reproduction and mobility and shortens lifespan. In the present study, we find that mdt-15 depletion or mutation specifically decreases membrane phospholipid unsaturation. Accordingly, mdt-15 worms exhibit disturbed ER homeostasis indicated by a constitutively activated ER unfolded protein response (UPRER). This stress response is only partially the consequence of reduced membrane lipid unsaturation, implicating other mdt-15–regulated processes in the protection against ER stress. Interestingly, mdt-15 inactivation or depletion of lipid metabolism enzymes SCD or sams-1 activates the UPRER without promoting misfolded protein aggregates in the ER. Moreover, these worms all exhibit wild-type sensitivity to chemically induced protein misfolding, and they do not display synthetic lethality with ire-1, whose inactivation causes protein misfolding. Therefore, the constitutive UPRER in mdt-15, SCD, or sams-1 worms is not the consequence of disturbed proteostasis, but likely the direct result from altered properties of the ER membrane. Altogether, our data suggest that the UPRER can be directly induced by membrane disequilibrium and thus acts as a circuit that comprehensively monitors ER homeostasis.

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