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Robust, synergistic regulation of human gene expression using TALE activators

Nature Methods volume 10, pages 243–245 (2013)Cite this article

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Abstract

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.

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Acknowledgements

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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Author notes

  1. Samantha J Linder and Deepak Reyon: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Morgan L Maeder, Samantha J Linder, Deepak Reyon, James F Angstman, Yanfang Fu, Jeffry D Sander & J Keith Joung

  2. Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Morgan L Maeder, Samantha J Linder, Deepak Reyon, James F Angstman, Yanfang Fu, Jeffry D Sander & J Keith Joung

  3. Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Morgan L Maeder, Samantha J Linder, Deepak Reyon, James F Angstman, Yanfang Fu, Jeffry D Sander & J Keith Joung

  4. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA

    Morgan L Maeder & J Keith Joung

  5. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    Deepak Reyon, Yanfang Fu, Jeffry D Sander & J Keith Joung

Authors
  1. Morgan L Maeder
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  2. Samantha J Linder
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  4. James F Angstman
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  5. Yanfang Fu
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  7. J Keith Joung
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Contributions

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.

Corresponding author

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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Supplementary Figures 1–2, Supplementary Tables 1–2, Supplementary Discussion (PDF 377 kb)

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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). https://doi.org/10.1038/nmeth.2366

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