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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.
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My lab is interested in gene regulation by the so-called Mediator complex, an essential eukaryotic transcriptional regulator that is mutated or deregulated in various human diseases (cancers, developmental disorders, etc). In particular, we study how Mediator and their associated transcriptional partners control stress responses (hypoxia, oxidative stress, starvation) and (lipid) metabolism. We use the powerful C. elegans model (the worm), mice (tissue-specific KO), and cell culture. We employ classic and state-of-the-art genetic, molecular, and genomic approaches (forward and reverse genetic screens, RNA-seq, CRISPR-Cas9, RNA interference, yeast-two-hybrid, etc). Projects revolve around characterizing how Mediator subunits and their transcription factor partners control metabolism and stress responses, identifying Mediator:transcription factor interactions, defining their molecular determinants to explore target ability by small molecule compounds, and to identify which cellular signalling pathways these factors interact with to regulate metabolism and stress adaptation. For more informatinon, see https://taubertlab.weebly.com.
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - May 2019)
No abstract available.
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.
Master's Student Supervision (2010 - 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.
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.
- Epigenetic regulator G9a provides glucose as a sweet key to stress resistance (2019)
PLOS Biology, 17 (4), e3000236
- Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity (2018)
Acta Neuropathologica Communications,
- NHR-49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting (2018)
Aging Cell, , e12743
- Genomic and Cytogenetic Characterization of a Balanced Translocation Disrupting NUP98 (2017)
Cytogenetic and Genome Research, 152 (3), 117--121
- The R148.3 Gene Modulates Caenorhabditis elegans Lifespan and Fat Metabolism (2017)
Genes|Genomes|Genetics, 7 (8), 2739--2747
- Bacterial diet affects vulval organogenesis in Caenorhabditis elegans Mediator kinase module mutants (2016)
- Caenorhabditis elegans Gets Metabolic Network Models (2016)
Cell Systems, 2 (5), 293--294
- eEF2K inhibition blocks Aβ42 neurotoxicity by promoting an NRF2 antioxidant response (2016)
Acta Neuropathologica, 133 (1), 101--119
- Gain-of-Function Alleles in Caenorhabditis elegans Nuclear Hormone Receptor nhr-49 Are Functionally Distinct (2016)
PLOS ONE, 11 (9), e0162708
- s-Adenosylmethionine Levels Govern Innate Immunity through Distinct Methylation-Dependent Pathways (2015)
Cell Metabolism, 22 (4), 633--645
- The Mediator complex of Caenorhabditis elegans: insights into the developmental and physiological roles of a conserved transcriptional coregulator (2015)
Nucleic Acids Research, 43 (4), 2442--2453
- The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans (2015)
Genetics, 202 (2), 583--599
- Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo (2014)
Proceedings of the National Academy of Sciences, 111 (22), E2271--E2280
- Membrane lipids and the endoplasmic reticulum unfolded protein response: An interesting relationship (2014)
Worm, 3 (3), e962405
- The C. elegans CDK8 Mediator module regulates axon guidance decisions in the ventral nerve cord and during dorsal axon navigation (2013)
Developmental Biology, 377 (2), 385--398
- The conserved Mediator subunit MDT-15 is required for oxidative stress responses in Caenorhabditis elegans (2013)
Aging Cell, 13 (1), 70--79
- Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships (2012)
PLoS Genetics, 8 (4), e1002645
- Function and Regulation of Lipid Biology in Caenorhabditis elegans Aging (2012)
Frontiers in Physiology, 3
- Repression of a Potassium Channel by Nuclear Hormone Receptor and TGF-β Signaling Modulates Insulin Signaling in Caenorhabditis elegans (2012)
PLoS Genetics, 8 (2), e1002519
- Somatic Differentiation and MR Imaging of Magnetically Labeled Human Embryonic Stem Cells (2012)
Cell Transplantation, 21 (12), 2555--2567
- Nuclear hormone receptors in nematodes: Evolution and function (2011)
Molecular and Cellular Endocrinology, 334 (1-2), 49--55
- Functional modularity of nuclear hormone receptors in a Caenorhabditis elegans metabolic gene regulatory network (2010)
Molecular Systems Biology, 6
- SET(BP1)-ing the stage for a better understanding of Schinzel-Giedion syndrome (2010)
Clinical Genetics, 78 (4), 348--349
- The Mediator Subunit MDT-15 Confers Metabolic Adaptation to Ingested Material (2008)
PLoS Genetics, 4 (2), e1000021
- Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans (2007)
Aging Cell, 6 (1), 95--110
- A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways in C. elegans (2006)
Genes & Development, 20 (9), 1137--1149
- E2F-Dependent Histone Acetylation and Recruitment of the Tip60 Acetyltransferase Complex to Chromatin in Late G1 (2004)
Molecular and Cellular Biology, 24 (10), 4546--4556
- MYC recruits the TIP60 histone acetyltransferase complex to chromatin (2003)
EMBO reports, 4 (6), 575--580
- Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation (2001)
Genes & Development, 15 (16), 2069--2082
- Function of the c-Myc oncoprotein in chromatin remodeling and transcription (2001)
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1471 (3), M135--M145
- Pleiotropic effects of cAMP on germination, antibiotic biosynthesis and morphological development inStreptomyces coelicolor (1998)
Molecular Microbiology, 30 (1), 33--46