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

Alejandro J. Brenes; Harunori Yoshikawa; Dalila Bensaddek; Bogdan Mirauta; Daniel D. Seaton; Jens Hukelmann; Hao Jiang; Oliver Stegle; Angus Lamond

doi:10.1016/j.celrep.2021.109032

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

Alejandro J. Brenes (Lead / Corresponding author), Harunori Yoshikawa, Dalila Bensaddek, Bogdan Mirauta, Daniel D. Seaton, Jens Hukelmann, Hao Jiang, Oliver Stegle, Angus Lamond

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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
Article number	109032
Number of pages	20
Journal	Cell Reports
Volume	35
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2021.109032
Publication status	Published - 27 Apr 2021

Keywords

RNA-seq
X chromosome inactivation
dosage compensation
erosion of X chromosome inactivation
gene expression
iPSC
mass spectrometry
proteome
proteomics
transcriptome

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.2021.109032Licence: CC BY

Final Published VersionFinal published version, 5.31 MBLicence: CC BY

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.",

keywords = "RNA-seq, X chromosome inactivation, dosage compensation, erosion of X chromosome inactivation, gene expression, iPSC, mass spectrometry, proteome, proteomics, transcriptome",

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

note = "This work was funded by the Wellcome Trust /MRC [098503/E/12/Z] and Wellcome Trust grants [073980/Z/03/Z, 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

AU - Bensaddek, Dalila

AU - Mirauta, Bogdan

AU - Seaton, Daniel D.

AU - Hukelmann, Jens

AU - Jiang, Hao

AU - Stegle, Oliver

AU - Lamond, Angus

N1 - This work was funded by the Wellcome Trust /MRC [098503/E/12/Z] and Wellcome Trust grants [073980/Z/03/Z, 105024/Z/14/Z] and supported by a UK Research Partnership Infrastructure Fund award to the Centre for Translational and Interdisciplinary Research.

PY - 2021/4/27

Y1 - 2021/4/27

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.

KW - RNA-seq

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KW - proteome

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KW - transcriptome

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Multidimensional Proteomic Analysis of Metabolic Stress & Cellular Phenotypes (Strategic Grant)

Human iPS Cell Collection (Joint with King's College London, Sanger Centre, European Bioinformatics Institute)

Aref#d: 15343. Structure and function of the mammalian cell nucleus (Principal Research Fellowship)

Towards population-scale proteomics to study molecular phenotypes in health and disease

Cite this

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Multidimensional Proteomic Analysis of Metabolic Stress & Cellular Phenotypes (Strategic Grant)

Human iPS Cell Collection (Joint with King's College London, Sanger Centre, European Bioinformatics Institute)

Aref#d: 15343. Structure and function of the mammalian cell nucleus (Principal Research Fellowship)

Student theses

Towards population-scale proteomics to study molecular phenotypes in health and disease

Cite this