Global variability in gene expression and alternative splicing is modulated by mitochondrial content
- Raul Guantes1,7,
- Alberto Rastrojo2,7,
- Ricardo Neves3,6,7,
- Ana Lima4,
- Begoña Aguado2 and
- Francisco J. Iborra3,5
- 1Department of Condensed Matter Physics, Materials Science Institute “Nicolás Cabrera” and Institute of Condensed Matter Physics (IFIMAC), Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid, Spain;
- 2Centro Biología Molecular “Severo Ochoa,” CSIC-UAM, Campus de Cantoblanco, 28049 Madrid, Spain;
- 3MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX3 9DS, United Kingdom;
- 4UC Biotech, Center for Neuroscience and Cell Biology, Biocant, Center of Innovation in Biotechnology, 3060-197 Cantanhede, Portugal;
- 5Centro Nacional de Biotecnología, CSIC, Campus de Cantoblanco, 28049 Madrid, Spain
- Corresponding author: fjiborra{at}cnb.csic.es
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↵7 These authors contributed equally to this work.
Abstract
Noise in gene expression is a main determinant of phenotypic variability. Increasing experimental evidence suggests that genome-wide cellular constraints largely contribute to the heterogeneity observed in gene products. It is still unclear, however, which global factors affect gene expression noise and to what extent. Since eukaryotic gene expression is an energy demanding process, differences in the energy budget of each cell could determine gene expression differences. Here, we quantify the contribution of mitochondrial variability (a natural source of ATP variation) to global variability in gene expression. We find that changes in mitochondrial content can account for ∼50% of the variability observed in protein levels. This is the combined result of the effect of mitochondria dosage on transcription and translation apparatus content and activities. Moreover, we find that mitochondrial levels have a large impact on alternative splicing, thus modulating both the abundance and type of mRNAs. A simple mathematical model in which mitochondrial content simultaneously affects transcription rate and splicing site choice can explain the alternative splicing data. The results of this study show that mitochondrial content (and/or probably function) influences mRNA abundance, translation, and alternative splicing, which ultimately affects cellular phenotype.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.178426.114.
- Received May 14, 2014.
- Accepted March 16, 2015.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
