Erosion of human X chromosome inactivation causes major remodeling 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

doi:10.1016/j.celrep.2021.109032

Erosion of human X chromosome inactivation causes major remodeling 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

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

X chromosome inactivation (XCI) is a dosage compensation mechanism in female mammals whereby transcription from one X chromosome is repressed. Analysis of human induced pluripotent stem cells (iPSCs) derived from female donors identified that low levels of XIST RNA correlated strongly with erosion of XCI. Proteomic analysis, RNA sequencing (RNA-seq), and polysome profiling showed that XCI erosion resulted in amplified RNA and protein expression from X-linked genes, providing a proteomic characterization of skewed dosage compensation. Increased protein expression was also detected from autosomal genes without an mRNA increase, thus altering the protein-RNA correlation between the X chromosome and autosomes. XCI-eroded lines display an ∼13% increase in total cell protein content, with increased ribosomal proteins, ribosome biogenesis and translation factors, and polysome levels. We conclude that XCI erosion in iPSCs causes a remodeling of the proteome, affecting the expression of a much wider range of proteins and disease-linked loci than previously realized.

Original language	English (US)
Pages (from-to)	109032
Journal	Cell reports
Volume	35
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2021.109032
State	Published - Apr 28 2021

Bibliographical note

KAUST Repository Item: Exported on 2021-05-03
Acknowledgements: We thank all of our collaborators who worked on the HipSci project as well as D. Cantrell, M. Stavridis, G. Findlay, J. Marchingo, and F. Dossin for all the insightful discussions. We would also like to thank L. Davidson within the University of Dundee Stem Cell Facility and all members of the Lamond Laboratory. This work was funded by the Wellcome Trust/MRC (098503/E/12/Z) and Wellcome Trust grants (073980/Z/03/Z and 105024/Z/14/Z) and supported by a UK Research Partnership Infrastructure Fund award to the Centre for Translational and Interdisciplinary Research.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2021.109032

https://repository.kaust.edu.sa/bitstream/10754/669034/1/1-s2.0-S2211124721003466-main.pdf

Cite this

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title = "Erosion of human X chromosome inactivation causes major remodeling of the iPSC proteome.",

abstract = "X chromosome inactivation (XCI) is a dosage compensation mechanism in female mammals whereby transcription from one X chromosome is repressed. Analysis of human induced pluripotent stem cells (iPSCs) derived from female donors identified that low levels of XIST RNA correlated strongly with erosion of XCI. Proteomic analysis, RNA sequencing (RNA-seq), and polysome profiling showed that XCI erosion resulted in amplified RNA and protein expression from X-linked genes, providing a proteomic characterization of skewed dosage compensation. Increased protein expression was also detected from autosomal genes without an mRNA increase, thus altering the protein-RNA correlation between the X chromosome and autosomes. XCI-eroded lines display an ∼13% increase in total cell protein content, with increased ribosomal proteins, ribosome biogenesis and translation factors, and polysome levels. We conclude that XCI erosion in iPSCs causes a remodeling of the proteome, affecting the expression of a much wider range of proteins and disease-linked loci than previously realized.",

author = "Brenes, {Alejandro J} and Harunori Yoshikawa and Dalila Bensaddek and Bogdan Mirauta and Daniel Seaton and Hukelmann, {Jens L} and Hao Jiang and Oliver Stegle and Lamond, {Angus I}",

note = "KAUST Repository Item: Exported on 2021-05-03 Acknowledgements: We thank all of our collaborators who worked on the HipSci project as well as D. Cantrell, M. Stavridis, G. Findlay, J. Marchingo, and F. Dossin for all the insightful discussions. We would also like to thank L. Davidson within the University of Dundee Stem Cell Facility and all members of the Lamond Laboratory. This work was funded by the Wellcome Trust/MRC (098503/E/12/Z) and Wellcome Trust grants (073980/Z/03/Z and 105024/Z/14/Z) and supported by a UK Research Partnership Infrastructure Fund award to the Centre for Translational and Interdisciplinary Research.",

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AU - Brenes, Alejandro J

AU - Yoshikawa, Harunori

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AU - Seaton, Daniel

AU - Hukelmann, Jens L

AU - Jiang, Hao

AU - Stegle, Oliver

AU - Lamond, Angus I

N1 - KAUST Repository Item: Exported on 2021-05-03 Acknowledgements: We thank all of our collaborators who worked on the HipSci project as well as D. Cantrell, M. Stavridis, G. Findlay, J. Marchingo, and F. Dossin for all the insightful discussions. We would also like to thank L. Davidson within the University of Dundee Stem Cell Facility and all members of the Lamond Laboratory. This work was funded by the Wellcome Trust/MRC (098503/E/12/Z) and Wellcome Trust grants (073980/Z/03/Z and 105024/Z/14/Z) and supported by a UK Research Partnership Infrastructure Fund award to the Centre for Translational and Interdisciplinary Research.

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N2 - X chromosome inactivation (XCI) is a dosage compensation mechanism in female mammals whereby transcription from one X chromosome is repressed. Analysis of human induced pluripotent stem cells (iPSCs) derived from female donors identified that low levels of XIST RNA correlated strongly with erosion of XCI. Proteomic analysis, RNA sequencing (RNA-seq), and polysome profiling showed that XCI erosion resulted in amplified RNA and protein expression from X-linked genes, providing a proteomic characterization of skewed dosage compensation. Increased protein expression was also detected from autosomal genes without an mRNA increase, thus altering the protein-RNA correlation between the X chromosome and autosomes. XCI-eroded lines display an ∼13% increase in total cell protein content, with increased ribosomal proteins, ribosome biogenesis and translation factors, and polysome levels. We conclude that XCI erosion in iPSCs causes a remodeling of the proteome, affecting the expression of a much wider range of proteins and disease-linked loci than previously realized.

AB - X chromosome inactivation (XCI) is a dosage compensation mechanism in female mammals whereby transcription from one X chromosome is repressed. Analysis of human induced pluripotent stem cells (iPSCs) derived from female donors identified that low levels of XIST RNA correlated strongly with erosion of XCI. Proteomic analysis, RNA sequencing (RNA-seq), and polysome profiling showed that XCI erosion resulted in amplified RNA and protein expression from X-linked genes, providing a proteomic characterization of skewed dosage compensation. Increased protein expression was also detected from autosomal genes without an mRNA increase, thus altering the protein-RNA correlation between the X chromosome and autosomes. XCI-eroded lines display an ∼13% increase in total cell protein content, with increased ribosomal proteins, ribosome biogenesis and translation factors, and polysome levels. We conclude that XCI erosion in iPSCs causes a remodeling of the proteome, affecting the expression of a much wider range of proteins and disease-linked loci than previously realized.

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Erosion of human X chromosome inactivation causes major remodeling of the iPSC proteome.

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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