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Erosion of human X chromosome inactivation causes major remodelling of the iPSC proteome

View ORCID ProfileAlejandro J. Brenes, Harunori Yoshikawa, Dalila Bensaddek, Bogdan Mirauta, Daniel Seaton, Jens L. Hukelmann, Hao Jiang, Oliver Stegle, Angus I. Lamond
doi: https://doi.org/10.1101/2020.03.18.997049
Alejandro J. Brenes
1Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow St, Dundee, DD1 5EH, United Kingdom
2Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dow St, Dundee, DD1 5EH, United Kingdom
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  • ORCID record for Alejandro J. Brenes
  • For correspondence: a.i.lamond@dundee.ac.uk ajbrenesmurillo@dundee.ac.uk
Harunori Yoshikawa
1Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow St, Dundee, DD1 5EH, United Kingdom
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Dalila Bensaddek
1Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow St, Dundee, DD1 5EH, United Kingdom
4Biosciences Core labs, Proteomics, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia
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Bogdan Mirauta
3European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, United Kingdom
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Daniel Seaton
3European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, United Kingdom
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Jens L. Hukelmann
1Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow St, Dundee, DD1 5EH, United Kingdom
5Immatics Biotechnologies, Paul-Ehrlich-Str. 15, Tuebingen, 72076, Germany
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Hao Jiang
1Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow St, Dundee, DD1 5EH, United Kingdom
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Oliver Stegle
3European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, United Kingdom
6Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany
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Angus I. Lamond
1Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow St, Dundee, DD1 5EH, United Kingdom
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  • For correspondence: a.i.lamond@dundee.ac.uk ajbrenesmurillo@dundee.ac.uk
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Summary

X chromosome inactivation (XCI) is a dosage compensation mechanism in female mammals whereby genes from one X chromosome are repressed. Analysis of human induced pluripotent stem cell (iPSC) lines using proteomics, RNAseq and polysome profiling showed a major change in the proteome upon XCI erosion. This resulted in amplified RNA and protein expression from X-linked genes. However, increased protein expression was also detected from autosomal genes without a corresponding mRNA increase, altering the protein-RNA correlation between genes on the X chromosome and autosomes. Eroded iPSC lines display ~13% increase in cell protein content, along with increased expression of ribosomal proteins, ribosome biogenesis and translation factors. They also showed significantly increased levels of active polysomes within the eroded lines. We conclude that erosion of XCI causes a major remodelling of the proteome, with translational mechanisms affecting the expression of a much wider range of proteins and disease-linked loci than previously realised.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Minor change to the title and abstract to best reflect the focus of the manuscript. The rest remains unchanged.

  • https://www.ebi.ac.uk/pride/archive/projects/PXD010557

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted May 07, 2020.
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Erosion of human X chromosome inactivation causes major remodelling of the iPSC proteome
Alejandro J. Brenes, Harunori Yoshikawa, Dalila Bensaddek, Bogdan Mirauta, Daniel Seaton, Jens L. Hukelmann, Hao Jiang, Oliver Stegle, Angus I. Lamond
bioRxiv 2020.03.18.997049; doi: https://doi.org/10.1101/2020.03.18.997049
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Erosion of human X chromosome inactivation causes major remodelling of the iPSC proteome
Alejandro J. Brenes, Harunori Yoshikawa, Dalila Bensaddek, Bogdan Mirauta, Daniel Seaton, Jens L. Hukelmann, Hao Jiang, Oliver Stegle, Angus I. Lamond
bioRxiv 2020.03.18.997049; doi: https://doi.org/10.1101/2020.03.18.997049

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