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

eLife

Minsi Zhang¹  Paul Ogrodowski¹  Craig B Thompson¹  Kevin Chen¹  Andrea Ventura¹  Bryan King¹  Gaspare La Rocca¹  Chiara Mastroleo¹  Xiaoyi Li²  Viviana Anelli³  Vincenzo Cavalieri⁴  Bing Shui⁵  Kevin Haigis⁵  Doron Betel⁶  Tullia Lindsten⁷  Joana Vidigal⁸  Kemal M Akat⁹  Thomas Tuschl⁹  Gunter Meister^1,10  Yilun Ma^1,11 

[1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, United States;Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, United States;Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, United States;Center of Integrative Biology, University of Trento, Trento, Italy;Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy;Department of Cancer Biology, Dana Farber Cancer Institute, Boston, United States;Hem/Oncology, Medicine and Institution for Computational Biomedicine, Weill Cornell Medical College, New York, United States;Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States;Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, Bethesda, United States;Laboratory of RNA Molecular Biology, The Rockefeller University, New York, United States;Regensburg Center for Biochemistry, University of Regensburg, Regensburg, Germany;Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, United States;

关键词: microRNA;    RISC;    argonaute;    T6B;    miRISC;    TNRC6;    Mouse;   

DOI  :  10.7554/eLife.70948

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY