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

Cell Rep. 2021 Apr 27;35(4):109032. doi: 10.1016/j.celrep.2021.109032.

Authors

Alejandro J Brenes¹, Harunori Yoshikawa², Dalila Bensaddek³, Bogdan Mirauta⁴, Daniel Seaton⁴, Jens L Hukelmann⁵, Hao Jiang⁶, Oliver Stegle⁷, Angus I Lamond⁸

Affiliations

¹ Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow St., Dundee DD1 5EH, UK; Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dow St., Dundee DD1 5EH, UK. Electronic address: ajbrenesmurillo@dundee.ac.uk.
² Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow St., Dundee DD1 5EH, UK; Division of Cell Signalling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
³ Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow St., Dundee DD1 5EH, UK; Biosciences Core Labs, Proteomics, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia.
⁴ European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton CB10 1SD, UK.
⁵ Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow St., Dundee DD1 5EH, UK; Immatics Biotechnologies, Paul-Ehrlich-Str. 15, Tuebingen 72076, Germany.
⁶ Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow St., Dundee DD1 5EH, UK.
⁷ European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton CB10 1SD, UK; European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany; Division of Computational Genomics and Systems Genetic, German Cancer Research Center, Heidelberg, Germany.
⁸ Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow St., Dundee DD1 5EH, UK. Electronic address: a.i.lamond@dundee.ac.uk.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Female
Humans
Induced Pluripotent Stem Cells / metabolism*
Proteome / metabolism*
X Chromosome Inactivation / genetics*

Substances

Proteome

Abstract

Publication types

MeSH terms

Substances

Grants and funding