Impact of Alternative Splicing on the Human Proteome
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Liu, Y., Gonzàlez-Porta, M., Santos, S., Brazma, A., Marioni, J., Aebersold, R., Venkitaraman, A., & et al. (2017). Impact of Alternative Splicing on the Human Proteome. Cell Reports, 20 (5), 1229-1241. https://doi.org/10.1016/j.celrep.2017.07.025
Alternative splicing is a critical determinant of genome complexity and, by implication, is assumed to engender proteomic diversity. This notion has not been experimentally tested in a targeted, quantitative manner. Here, we have developed an integrative approach to ask whether perturbations in mRNA splicing patterns alter the composition of the proteome. We integrate RNA sequencing (RNA-seq) (to comprehensively report intron retention, differential transcript usage, and gene expression) with a data-independent acquisition (DIA) method, SWATH-MS (sequential window acquisition of all theoretical spectra-mass spectrometry), to capture an unbiased, quantitative snapshot of the impact of constitutive and alternative splicing events on the proteome. Whereas intron retention is accompanied by decreased protein abundance, alterations in differential transcript usage and gene expression alter protein abundance proportionate to transcript levels. Our findings illustrate how RNA splicing links isoform expression in the human transcriptome with proteomic diversity and provides a foundation for studying perturbations associated with human diseases.
RNA, alternative splicing, proteomics
We gratefully acknowledge funding from the EMBL (to M.G.-P. and J.C.M.), the NIH (U01CA152813 to Y.S.L. and R.A.), the ERC (AdG-670821 [Proteomics 4D] to R.A.), the Swiss National Science Foundation (31003A_166435 to R.A.), SystemsX.ch through project PhosphonetX-PPM (to R.A.), the UK Medical Research Council (G1001521, G1001522, and 4050551988 to A.R.V.), and the NHMRC (1127745 to V.O.W.). V.O.W. is supported by an innovation fellowship from VESKI.
Medical Research Council (MC_UU_12022/1)
External DOI: https://doi.org/10.1016/j.celrep.2017.07.025
This record's URL: https://www.repository.cam.ac.uk/handle/1810/267388
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