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microRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis

Albertomaria Moro, Tristan Discroll, William Armero, Liana C. Boraas, Dionna M. Kasper, Nicolas Baeyens, Charlene Jouy, Venkatesh Mallikarjun, Joe Swift, Sang Joon Ahn, Donghoon Lee, Jing Zhang, Mengting Gu, Mark Gerstein, Martin Schwart, Stefania Nicoli
doi: https://doi.org/10.1101/359521
Albertomaria Moro
1Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, CT 06511, USA
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Tristan Discroll
1Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, CT 06511, USA
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William Armero
1Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, CT 06511, USA
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Liana C. Boraas
1Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, CT 06511, USA
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Dionna M. Kasper
1Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, CT 06511, USA
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Nicolas Baeyens
2Wellcome Trust Centre for Cell-Matrix Research
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Charlene Jouy
2Wellcome Trust Centre for Cell-Matrix Research
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Venkatesh Mallikarjun
2Wellcome Trust Centre for Cell-Matrix Research
3Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, UK
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Joe Swift
2Wellcome Trust Centre for Cell-Matrix Research
3Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9PL, UK
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Sang Joon Ahn
1Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, CT 06511, USA
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Donghoon Lee
4Program in Computational Biology and Bioinformatics,
5Department of Molecular Biophysics and Biochemistry,
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Jing Zhang
4Program in Computational Biology and Bioinformatics,
5Department of Molecular Biophysics and Biochemistry,
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Mengting Gu
4Program in Computational Biology and Bioinformatics,
5Department of Molecular Biophysics and Biochemistry,
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Mark Gerstein
4Program in Computational Biology and Bioinformatics,
5Department of Molecular Biophysics and Biochemistry,
6Department of Computer Science, Yale University, New Haven, CT 06520, USA
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Martin Schwart
1Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, CT 06511, USA
2Wellcome Trust Centre for Cell-Matrix Research
9Departments of Cell Biology and Biomedical Engineering, Yale University
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  • For correspondence: martin.schwartz@yale.edu stefania.nicoli@yale.edu
Stefania Nicoli
1Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale University School of Medicine, New Haven, CT 06511, USA
7Department of Genetics,
8Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA
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  • For correspondence: martin.schwartz@yale.edu stefania.nicoli@yale.edu
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Summary

The mechanical properties of tissues, which are determined primarily by their extracellular matrix (ECM), are largely stable over time despite continual turnover of ECM constituents 1,2. These observations imply active homeostasis, where cells sense and adjust rates of matrix synthesis, assembly and degradation to keep matrix and tissue properties within the optimal range. However, the regulatory pathways that mediate this process are essentially unknown3. Genome-wide analyses of endothelial cells revealed abundant microRNA-mediated regulation of cytoskeletal, adhesive and extracellular matrix (CAM) mRNAs. High-throughput assays showed co-transcriptional regulation of microRNA and CAM genes on stiff substrates, which buffers CAM expression. Disruption of global or individual microRNA-dependent suppression of CAM genes induced hyper-adhesive, hyper-contractile phenotypes in multiple systems in vitro, and increased tissue stiffness in the zebrafish fin-fold during homeostasis and regeneration in vivo. Thus, a network of microRNAs and CAM mRNAs mediate tissue mechanical homeostasis.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 03, 2018.
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microRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis
Albertomaria Moro, Tristan Discroll, William Armero, Liana C. Boraas, Dionna M. Kasper, Nicolas Baeyens, Charlene Jouy, Venkatesh Mallikarjun, Joe Swift, Sang Joon Ahn, Donghoon Lee, Jing Zhang, Mengting Gu, Mark Gerstein, Martin Schwart, Stefania Nicoli
bioRxiv 359521; doi: https://doi.org/10.1101/359521
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microRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis
Albertomaria Moro, Tristan Discroll, William Armero, Liana C. Boraas, Dionna M. Kasper, Nicolas Baeyens, Charlene Jouy, Venkatesh Mallikarjun, Joe Swift, Sang Joon Ahn, Donghoon Lee, Jing Zhang, Mengting Gu, Mark Gerstein, Martin Schwart, Stefania Nicoli
bioRxiv 359521; doi: https://doi.org/10.1101/359521

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