Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Synergistic and tunable human gene activation by combinations of synthetic transcription factors


Mammalian genes are regulated by the cooperative and synergistic actions of many transcription factors. In this study we recapitulate this complex regulation in human cells by targeting endogenous gene promoters, including regions of closed chromatin upstream of silenced genes, with combinations of engineered transcription activator–like effectors (TALEs). These combinations of TALE transcription factors induced substantial gene activation and allowed tuning of gene expression levels that will broadly enable synthetic biology, gene therapy and biotechnology.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Synergistic activation of gene expression by combinations of TALE-TFs.
Figure 2: Combinatorial regulation of gene expression by TALE-TFs.


  1. Guido, N.J. et al. Nature 439, 856–860 (2006).

    Article  CAS  Google Scholar 

  2. Guet, C.C., Elowitz, M.B., Hsing, W. & Leibler, S. Science 296, 1466–1470 (2002).

    Article  CAS  Google Scholar 

  3. Cox, R.S. III., Surette, M.G. & Elowitz, M.B. Mol. Syst. Biol. 3, 145 (2007).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Ausländer, S., Ausländer, D., Müller, M., Wieland, M. & Fussenegger, M. Nature 487, 123–127 (2012).

    Article  Google Scholar 

  6. Tamsir, A., Tabor, J.J. & Voigt, C.A. Nature 469, 212–215 (2011).

    Article  CAS  Google Scholar 

  7. Moscou, M.J. & Bogdanove, A.J. Science 326, 1501 (2009).

    Article  CAS  Google Scholar 

  8. Boch, J. et al. Science 326, 1509–1512 (2009).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    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. Streubel, J., Blucher, C., Landgraf, A. & Boch, J. Nat. Biotechnol. 30, 593–595 (2012).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Joung, J.K., Koepp, D.M. & Hochschild, A. Science 265, 1863–1866 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Beerli, R.R., Dreier, B. & Barbas, C.F. III. Proc. Natl. Acad. Sci. USA 97, 1495–1500 (2000).

    Article  CAS  Google Scholar 

Download references


This work was supported by a US National Institutes of Health (NIH) Director's New Innovator Award (DP2-OD008586), a National Science Foundation (NSF) Faculty Early Career Development (CAREER) Award (CBET-1151035), NIH R03-AR061042, The Hartwell Foundation Individual Biomedical Research Award and a March of Dimes Basil O'Connor Starter Scholar Award to C.A.G.; grants from the NIH (P50-GM081883) and the Defense Advance Research Projects Agency (HR0011-09-1-0040) to A.J.H.; and grants from the NIH to G.E.C. (U54-HG004563) and F.G. (R01-AR048852). D.G.O. was supported by a predoctoral fellowship from the American Heart Association. K.A.G. was supported by an NSF Graduate Research Fellowship.

Author information

Authors and Affiliations



P.P.-P., A.M.F., G.E.C., A.J.H. and C.A.G. designed experiments. P.P.-P., D.G.O., J.M.B., A.M.F. and K.A.G. performed the experiments. P.P.-P., F.G., G.E.C., A.J.H. and C.A.G. analyzed the data. P.P.-P. and C.A.G. wrote the manuscript.

Corresponding author

Correspondence to Charles A Gersbach.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 1–3 (PDF 6092 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Perez-Pinera, P., Ousterout, D., Brunger, J. et al. Synergistic and tunable human gene activation by combinations of synthetic transcription factors. Nat Methods 10, 239–242 (2013).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing