Inducible and reversible inhibition of miRNA-mediated gene repression in vivo
- Memorial Sloan Kettering Cancer Center, United States
- Dana Farber Cancer Institute, United States
- Rockefeller University, United States
- University of Palermo, Italy
- Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, United States
- Center of Integrative Biology, University of Trento, Italy
- Weill Cornell Medical College, United States
- NCI, NIH, United States
- Max Planck Institute of Biochemistry, Germany
- Memorial Sloan-Kettering Cancer Center, United States
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.
Data availability
Processed sequencing data are included as source data. Fastq files have been deposited to GEO (GEO accession number: GSE179588)
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A mouse tissue atlas of small noncoding RNA.NCBI Gene Expression Omnibus, GSE119661.
Article and author information
Author details
Funding
National Cancer Institute (R01CA149707)
- Andrea Ventura
National Cancer Institute (R01CA245507)
- Andrea Ventura
National Cancer Institute (P30 CA008748)
- Craig B Thompson
Starr Foundation (NA)
- Gaspare La Rocca
- Tullia Lindsten
- Andrea Ventura
National Institute of General Medical Sciences (T32GM007739)
- Yilun Ma
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Ashish Lal, National Institutes of Health, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#10-10-022) of Memorial Sloan Kettering Cancer Center
Version history
- Preprint posted: June 1, 2021 (view preprint)
- Received: June 3, 2021
- Accepted: August 24, 2021
- Accepted Manuscript published: August 31, 2021 (version 1)
- Version of Record published: September 27, 2021 (version 2)
Copyright
© 2021, La Rocca et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Inducible and reversible inhibition of miRNA-mediated gene repression in vivo
eLife 10:e70948.
https://doi.org/10.7554/eLife.70948
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