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Robust, synergistic regulation of human gene expression using TALE activators


Artificial activators designed using transcription activator–like effector (TALE) technology have broad utility, but previous studies suggest that these monomeric proteins often exhibit low activities. Here we demonstrate that TALE activators can robustly function individually or in synergistic combinations to increase expression of endogenous human genes over wide dynamic ranges. These findings will encourage applications of TALE activators for research and therapy, and guide design of monomeric TALE-based fusion proteins.

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Figure 1: Activities of 54 variable-length TALE activators targeted to the endogenous human VEGFA gene.
Figure 2: Activities of VP64 and p65 TALE activators targeted to the endogenous human VEGFA, miR-302/367 cluster and NTF3.


  1. Joung, J.K. & Sander, J.D. Nat. Rev. Mol. Cell Biol. 14, 49–55 (2012).

    Article  Google Scholar 

  2. Mussolino, C. & Cathomen, T. Curr. Opin. Biotechnol. 23, 644–650 (2012).

    Article  CAS  Google Scholar 

  3. Miller, J.C. et al. Nat. Biotechnol. 29, 143–148 (2011).

    Article  CAS  Google Scholar 

  4. Zhang, F. et al. Nat. Biotechnol. 29, 149–153 (2011).

    Article  Google Scholar 

  5. Geissler, R. et al. PLoS ONE 6, e19509 (2011).

    Article  CAS  Google Scholar 

  6. Garg, A., Lohmueller, J.J., Silver, P.A. & Armel, T.Z. Nucleic Acids Res. 40, 7584–7595 (2012).

    Article  CAS  Google Scholar 

  7. Tremblay, J.P., Chapdelaine, P., Coulombe, Z. & Rousseau, J. Hum. Gene Ther. 23, 883–890 (2012).

    Article  CAS  Google Scholar 

  8. Wang, Z. et al. Angew. Chem. Int. Edn. Engl. 51, 8505–8508 (2012).

    Article  CAS  Google Scholar 

  9. Cong, L., Zhou, R., Kuo, Y.C., Cunniff, M. & Zhang, F. Nat. Commun. 3, 968 (2012).

    Article  Google Scholar 

  10. Bultmann, S. et al. Nucleic Acids Res. 40, 5368–5377 (2012).

    Article  CAS  Google Scholar 

  11. Cermak, T. et al. Nucleic Acids Res. 39, e82 (2011).

    Article  CAS  Google Scholar 

  12. Reyon, D. et al. Nat. Biotechnol. 30, 460–465 (2012).

    Article  CAS  Google Scholar 

  13. Liu, P.Q. et al. J. Biol. Chem. 276, 11323–11334 (2001).

    Article  CAS  Google Scholar 

  14. Carey, M., Lin, Y.S., Green, M.R. & Ptashne, M. Nature 345, 361–364 (1990).

    Article  CAS  Google Scholar 

  15. Khalil, A.S. et al. Cell 150, 647–658 (2012).

    Article  CAS  Google Scholar 

  16. Deans, T.L., Cantor, C.R. & Collins, J.J. Cell 130, 363–372 (2007).

    Article  CAS  Google Scholar 

  17. Tigges, M., Marquez-Lago, T.T., Stelling, J. & Fussenegger, M. Nature 457, 309–312 (2009).

    Article  CAS  Google Scholar 

  18. Xie, Z., Wroblewska, L., Prochazka, L., Weiss, R. & Benenson, Y. Science 333, 1307–1311 (2011).

    Article  CAS  Google Scholar 

  19. Culler, S.J., Hoff, K.G. & Smolke, C.D. Science 330, 1251–1255 (2010).

    Article  CAS  Google Scholar 

  20. Auslander, S., Auslander, D., Muller, M., Wieland, M. & Fussenegger, M. Nature 487, 123–127 (2012).

    Article  Google Scholar 

  21. Rosenbloom, K.R. et al. Nucleic Acids Res. 40, D912–D917 (2012).

    Article  CAS  Google Scholar 

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This work was supported by a US National Institutes of Health (NIH) Director's Pioneer Award DP1 OD006862 (J.K.J.), NIH P50 HG005550 and R01 NS073124 (J.K.J.), the Jim and Ann Orr Massachusetts General Hospital Research Scholar Award (J.K.J.), a US National Science Foundation Graduate Research Fellowship (M.L.M.), and NIH T32 CA009216 (J.D.S.). We thank J. Foley for technical assistance with construction of TALE-activator plasmids, R. Mylvaganam for technical assistance with flow cytometry, and the Massachusetts General Hospital Nucleic Acid Quantitation Core (supported by NIH P30 NS45776) for assistance with performing real-time reverse-transcription–PCR assays.

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M.L.M., S.J.L., D.R., J.F.A., Y.F., J.D.S. and J.K.J. designed the experiments. M.L.M., S.J.L., D.R., J.F.A. and Y.F. performed experiments. M.L.M. and J.K.J. wrote the manuscript.

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Correspondence to J Keith Joung.

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Competing interests

J.K.J. has a financial interest in Transposagen Biopharmaceuticals. J.K.J.'s interests were reviewed and are managed by Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies.

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Maeder, M., Linder, S., Reyon, D. et al. Robust, synergistic regulation of human gene expression using TALE activators. Nat Methods 10, 243–245 (2013).

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