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Mechanisms of transcription regulation in human development and disease

The Taatjes lab seeks to discoverÌýmolecular mechanisms that control human gene expression, and how transcription and signaling pathways are altered during development and disease.Ìý We focus on sequence-specific, DNA-binding transcription factors (TFs) and the Pre-Initiation Complex (PIC), whichÌýconsists of Mediator, RNA polymerase II (pol II), TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH.ÌýÌýThe PIC controls the activity of the pol II enzyme, which transcribes all protein-coding genes and most non-coding RNAs in the human genome.ÌýÌýWithin the PIC, the 1.4 MDa Mediator complex, the 1.3 MDa TFIID complex, and the 0.5 MDa TFIIH complex help regulate pol II activity in ways that remain poorly understood.ÌýÌýAt a basic level, TFIIH regulates transcription initiation and post-initiation steps (e.g. RNA processing), whereas Mediator and TFIID function by converting biological inputs (communicated by TFs) to physiological responses (via changes in gene expression).ÌýÌýWe utilize a variety of experimental techniques that include biochemical, biophysical, molecular and cell biology approaches, as well as metabolomics, proteomics, and transcriptomics.

³§±ð±ðÌýÌýfor a full and up-to-date list

• Allen, BL; Quach, K; Jones, T; Levandowski, CB; Ebmeier, CC; Rubin, JD; Read, T; Dowell, RD; Schepartz, A*; Taatjes, DJ*.Ìý Suppression of p53 response by targeting p53–Mediator binding with a stapled peptide. Cell Rep 2022, 39: 110630.Ìý
• Levandowski, CB; Jones, T; Gruca, M; Ramamoorthy, S; Dowell, RD;* Taatjes, DJ.*Ìý The D40p53 isoform inhibits p53-dependent eRNA transcription and enables regulation by signal-specific transcription factors during p53 activation. PLoS Biol 2021, 19: e3001364.Ìý
• Rimel, JK; Poss, ZC; Erickson, B; Maas, ZL; Ebmeier, CC; Johnson, JL; Decker, T-M; Yaron, TM; Bradley, MJ; Hamman, KB; Hu, S; Malojcic, G; Marineau, JJ; White, PW; Brault, M.; Tao, L.; DeRoy, P; Clavette, C; Nayak, S; Damon, LJ; Kaltheuner, IH; Bunch, H; Cantley, LC; Geyer, M; Iwasa, J; Dowell, RD; Bentley, DL; Old WM;* Taatjes, DJ.*Ìý Selective inhibition of CDK7 reveals high-confidence targets and novel mechanisms for TFIIH function in transcription. Genes Dev 2020, 34: 1452 – 1473.
• Fant, CB; Levandowski, CB; Gupta, K; Maas, ZL; Moir, JT; Rubin, JD; Sawyer, A; Esbin, M; Rimel, JK; Luyties, O; Marr, MT; Berger, I; Dowell, RD; Taatjes, DJ. TFIID enables RNA polymerase II promoter-proximal pausing. Mol Cell 2020, 78: 785 – 793.
• Guo, YE; Manteiga, JC; Henninger, J; Sabari, BR; Dall'Agnese, A; Hannett, NM; Spille, J-H; Afeyan, LK; Zamudio, AV;Ìý Shrinivas, K; Abraham, BJ; Boija, A; Decker, TM; Rimel, JK; Fant, CB; Lee, TI; Cisse, II; Sharp, PA; Taatjes, DJ; Young, RA. RNA polymerase II phosphorylation regulates a switch between transcriptional and splicing condensates. Nature 2019, 572: 543 – 548.Ìý
• Steinparzer, I; Sedlyarov, V; Rubin, JD; Eislmayr, K; Galbraith MD; Levandowski, CB; Vcelkova, T; Sneezum, L; Wascher, F; Amman, F; Kleinova, R; Bender, H; Andrysik, Z; Espinosa, JM; Superti-Furga, G; Dowell, RD; Taatjes, DJ;* Kovarik, P.*Ìý Transcriptional responses to IFNg require Mediator kinase-dependent pause release and mechanistically distinct CDK8 and CDK19 functions. Mol Cell 2019, 76: 485 – 499.Ìý
• Boija, A; Klein, IA; Sabari, BR; Dall'Agnese, A; Coffey, EL; Zamudio, AV; Li, CH; Shrinivas, K; Manteiga, J; Hannett, NM; Abraham, BJ; Schuijers, J; Afeyan, L; Guo, YE; Rimel, JK; Fant, CB; Lee, TI; Taatjes, DJ; Young, RA. Transcription factors activate genes through the phase separation capacity of their activation domains. Cell 2018, 175: 1842 – 1855.Ìý
• Ebmeier, CC; Erickson, B; Allen, BL; Allen, MA; Kim, H; Fong, N; Jacobsen, JR; Liang, K; Shilatifard, A; Dowell, RD; Old, WM; Bentley, DL*; Taatjes, DJ*. Human TFIIH kinase CDK7 regulates transcription-associated chromatin modifications. Cell Rep 2017, 20: 1173 - 1186.Ìý
• Poss, ZC; Ebmeier, CC; Odell, AT; Tangpeerachaikul, A; Lee, T; Pelish, HE; Shair, MD; Dowell, RD; Old, WM; Taatjes, DJ.Ìý Identification of Mediator kinase substrates in human cells using cortistatin A and quantitative phosphoproteomics. Cell Rep 2016, 15: 436 – 450.Ìý
• Pelish, HE; Liau, BB; Nitulescu, I; Tangpeerachaikul, A; Poss, ZC; DaSilva, D; Caruso, B; Arefolov, A; Fadeyi, O; Christie, A; Du, K; Banka, D; Schneider, EV; Jestel, A; Zou, G; Si, C; Ebmeier, CC; Bronson, RT; Krivtsov, AV; Myers, AG; Kohl, N; Kung, A; Armstrong, S; Lemieux, M; Taatjes, DJ; Shair, MD. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature 2015, 526: 273 – 276.

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Selected Review articles:

• Nayak, S; Taatjes DJ. SnapShot: Mediator Complex Structure. Cell 2022, 185: 3458.
• Clopper, KC; Taatjes, DJ. Chemical inhibitors of transcription-associated kinases. Curr Opin Chem Biol 2022, 70: 102186.Ìý
• Richter, WF; Nayak, S; Iwasa, J; Taatjes, DJ. The Mediator complex as a master regulator of transcription by RNA polymerase II. Nat Rev Mol Cell Biol 2022, 23: 732 - 749.
• Luyties, O; Taatjes, DJ.Ìý The Mediator kinase module: an interface between cell signaling and transcription. Trends Biochem Sci 2022, 47: 314 - 327.Ìý
• Palacio, M; Taatjes DJ. Merging established mechanisms with new insights: Condensates, hubs, and the regulation of RNA polymerase II transcription. J Mol Biol 2022, 433: 167216.Ìý
• Schier, AC; Taatjes, DJ. Structure and mechanism of the RNA polymerase II transcription machinery. Genes Dev 2020, 34: 465 – 488.
• Rimel, JK; Taatjes, DJ. The essential and multi-functional TFIIH complex. Protein Sci 2018, 27: 1018 - 1037.Ìý