Global variability in gene expression and alternative splicing is modulated by mitochondrial content

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 phenotypeThe authors would like to thank the Ministerio de Economia y Competitividad (Spain) (Grant numbers BFU2009-10792 and BFU2013-45918-R) and The Medical Research Council (U.K.) for supporting this work. We thank the Fundação Ciência e Tecnologia (Portugal) for funding R.P.N. A.R. held a postgraduate fellowship (FPU) from the Ministerio de Educación y Ciencia. The CBMSO receives an institutional grant from Fundación Ramón Arece

Global variability in gene expression and alternative splicing is modulated by mitochondrial content

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.The authors would like to thank the Ministerio de Economia y Competitividad (Spain) (Grant numbers BFU2009-10792 and BFU2013-45918-R) and The Medical Research Council (U.K.) for supporting this work. We thank the Fundação Ciência e Tecnologia (Portugal) for funding R.P.N. A.R. held a postgraduate fellowship (FPU) from the Ministerio de Educación y Ciencia.Peer Reviewe