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Inducible and reversible inhibition of miRNA-mediated gene repression in vivo

View ORCID ProfileGaspare La Rocca, View ORCID ProfileBryan King, Bing Shui, View ORCID ProfileXiaoyi Li, Minsi Zhang, Kemal Akat, Paul Ogrodowski, Chiara Mastroleo, Kevin Chen, Vincenzo Cavalieri, View ORCID ProfileYilun Ma, View ORCID ProfileViviana Anelli, View ORCID ProfileDoron Betel, View ORCID ProfileJoana A. Vidigal, View ORCID ProfileThomas Tuschl, Gunter Meister, Craig B. Thompson, Tullia Lindsten, View ORCID ProfileKevin M. Haigis, View ORCID ProfileAndrea Ventura
doi: https://doi.org/10.1101/2021.06.01.445680
Gaspare La Rocca
1Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Bryan King
1Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Bing Shui
2Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
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Xiaoyi Li
1Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
3Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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Minsi Zhang
1Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Kemal Akat
4Laboratory of RNA Molecular Biology, The Rockefeller University, New York, NY, USA
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Paul Ogrodowski
1Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Chiara Mastroleo
1Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Kevin Chen
1Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Vincenzo Cavalieri
5Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy
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Yilun Ma
6Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY, USA
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Viviana Anelli
7Center of Integrative Biology, University of Trento, Trento, Italy
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Doron Betel
8Hem/Oncology, Medicine and Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA
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Joana A. Vidigal
9Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, Bethesda, MD, USA
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Thomas Tuschl
4Laboratory of RNA Molecular Biology, The Rockefeller University, New York, NY, USA
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Gunter Meister
10Regensburg Center for Biochemistry, University of Regensburg, Germany
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Craig B. Thompson
1Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Tullia Lindsten
11Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Kevin M. Haigis
2Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
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Andrea Ventura
1Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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  • For correspondence: aventura71@gmail.com
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Abstract

Although virtually all gene networks are predicted to be controlled by miRNAs, the contribution of this important layer of gene regulation to tissue homeostasis in adult animals remains unclear. Gain and loss of function experiments have provided key insights into the specific function of individual miRNAs, but effective genetic tools to study the functional consequences of global inhibition of miRNA activity in vivo are lacking. Here we report the generation and characterization of a genetically engineered mouse strain in which miRNA-mediated gene repression can be reversibly inhibited without affecting miRNA biogenesis or abundance. We demonstrate the usefulness of this strategy by investigating the consequences of acute inhibition of miRNA function in adult animals. We find that different tissues and organs respond differently to global loss of miRNA function. While miRNA-mediated gene repression is essential for the homeostasis of the heart and the skeletal muscle, it is largely dispensable in the majority of other organs. Even in tissues where it is not required for homeostasis, such as the intestine and hematopoietic system, miRNA activity can become essential during regeneration following acute injury. These data support a model where many metazoan tissues primarily rely on miRNA function to respond to potentially pathogenic events.

Competing Interest Statement

C.B.T. is a founder of Agios Pharmaceuticals and a member of its scientific advisory board. He is also a former member of the Board of Directors and stockholder of Merck and Charles River Laboratories. He holds patents related to cellular metabolism.

Footnotes

  • ↵✉ email: laroccag{at}mskcc.org; venturaa{at}mskcc.org

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 01, 2021.
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Inducible and reversible inhibition of miRNA-mediated gene repression in vivo
Gaspare La Rocca, Bryan King, Bing Shui, Xiaoyi Li, Minsi Zhang, Kemal Akat, Paul Ogrodowski, Chiara Mastroleo, Kevin Chen, Vincenzo Cavalieri, Yilun Ma, Viviana Anelli, Doron Betel, Joana A. Vidigal, Thomas Tuschl, Gunter Meister, Craig B. Thompson, Tullia Lindsten, Kevin M. Haigis, Andrea Ventura
bioRxiv 2021.06.01.445680; doi: https://doi.org/10.1101/2021.06.01.445680
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Inducible and reversible inhibition of miRNA-mediated gene repression in vivo
Gaspare La Rocca, Bryan King, Bing Shui, Xiaoyi Li, Minsi Zhang, Kemal Akat, Paul Ogrodowski, Chiara Mastroleo, Kevin Chen, Vincenzo Cavalieri, Yilun Ma, Viviana Anelli, Doron Betel, Joana A. Vidigal, Thomas Tuschl, Gunter Meister, Craig B. Thompson, Tullia Lindsten, Kevin M. Haigis, Andrea Ventura
bioRxiv 2021.06.01.445680; doi: https://doi.org/10.1101/2021.06.01.445680

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