Ph.D.: Organic Chemistry; Advisor: Dr. Tad Koch. University of Colorado at Boulder, 1994-1998
Postdoctoral Fellow: Molecular and Structural Biology; Advisor: Dr. Robert Tjian. University of California at Berkeley, 1999-2004
Structure and Mechanism of the human Transcription Machinery
The Taatjes lab investigates the molecular mechanisms by which the human transcription machinery functions and is regulated. Proper regulation of gene expression is fundamental to every major physiological process, and changes in gene expression patterns are hallmarks of human development and disease. Consequently, the questions that we address in the Taatjes lab are fundamental and of broad significance. At the moment, our research has direct implications for heart disease and development, mental/neuronal development, cancer, diabetes, and aging.
The macromolecular assembly required to initiate gene expression consists of 8 protein complexes and is approximately 3.5 MDa in size. The human Mediator complex is a major sub-assembly within the transcription apparatus and represents the main focus of the lab. Although the mechanisms by which Mediator functions to control gene expression are poorly-defined, it is clear that Mediator is essential for expression of virtually all protein-coding genes and regulates both transcription initiation and elongation. Mediator remains poorly understood in part because Mediator structure and even its composition can change, depending upon the context. Combined with the sheer size of the human Mediator complex (26 subunits, 1.2 MDa), this structural adaptability bestows seemingly unlimited regulatory potential within the complex. Our lab uses an array of diverse experimental approaches, ranging from basic biochemistry (protein expression and purification, enzymatic assays, in vitro transcription), mass spectrometry (MudPIT, linear ion-trap MS, plus top-down MS approaches), structural biology (cryo-electron microscopy, X-ray crystallography and/or NMR), and cell-based assays (ChIP, RT-QPCR, microarray, RNAi, ChIP-Seq), to study human gene expression, with a focus on Mediator-specific regulatory mechanisms. Importantly, we have biochemically purified each of the other factors that, together with Mediator, comprise the fully-functional, 3.5 MDa human transcription apparatus (which includes RNA polymerase II, TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH). This enables us to address very specific mechanistic questions regarding Mediator’s role as a genome-wide regulator of transcription.
He, Y; Fang, J; Taatjes, DJ; Nogales, E. Structural visualization of key steps in human transcription initiation. Nature2013, 495: 481 – 486.
Bancerek, J; Poss, ZC; Steinparzer, I; Sedlyarov, V; Pfaffenwimmer, T; Mikulic, I; Dolken, L; Strobl, B; Muller, M; Taatjes, DJ; Kovarik, P. CDK8 Kinase Phosphorylates Transcription Factor STAT1 to Selectively Regulate the Interferon Response. Immunity2013, 38: 250 – 262.
Bernecky, C; Grob, P; Ebmeier, CC; Nogales, E; Taatjes, DJ. Molecular architecture of the human Mediator–RNA Polymerase II–TFIIF assembly. PLoS Biol. 2011, 9: e1000603.
Kagey, MH; Newman, JJ; Bilodeau, S; Zhan, Y; Orlando, DA; van Berkum, NL; Ebmeier, CC; Goossens, J; Rahl, PB; Levine, SS; Taatjes, DJ; Dekker, J; Young, RA. Mediator and Cohesin connect gene expression and chromatin architecture. Nature. 2010, 467: 430-435.
Ebmeier, CC; Taatjes, DJ. Activator-Mediator binding regulates Mediator-cofactor interactions. Proc Natl Acad Sci. USA. 2010, 107: 11283-11288.
Meyer, KD; Lin, S; Bernecky, C; Gao, Y; Taatjes, DJ. p53 activates transcription by directing structural shifts in Mediator. Nat Struct Mol Biol. 2010, 17: 753-760.
Taatjes, DJ. The human Mediator complex: a versatile, genome-wide regulator of transcription. Trends Biochem Sci. 2010, 35: 315-322.
Donner, AJ; Ebmeier, CC; Taatjes, DJ; Espinosa JM. CDK8 is a positive regulator of transcriptional elongation within the serum response network. Nat Struct Mol Biol. 2010, 17: 194-201.
Knuesel, MT; Meyer, KD; Bernecky, C; Taatjes, DJ. The human CDK8 subcomplex is a molecular switch that controls Mediator co-activator function. Genes & Dev. 2009, 23: 439-451.
Knuesel, MT; Meyer, KD; Donner, AJ; Espinosa JM; Taatjes, DJ. The human CDK8 subcomplex is a histone kinase that requires Med12 for activity and can function independently of Mediator. Mol Cell Biol. 2009, 29: 650-661.
Meyer, KD; Donner, AJ; Knuesel, MT; York, AG; Espinosa, JM; Taatjes, DJ. Cooperative activity of CDK8 and GCN5L within Mediator directs tandem phosphoacetylation of histone H3. EMBO J 2008, 27: 1447-1457.