Landscape of X chromosome inactivation across human tissues

Taru Tukiainen, Alexandra Chloé Villani, Angela Yen, Manuel A. Rivas, Jamie L. Marshall, Rahul Satija, Matt Aguirre, Laura Gauthier, Mark Fleharty, Andrew Kirby, Beryl B. Cummings, Stephane E. Castel, Konrad J. Karczewski, François Aguet, Andrea Byrnes, Tuuli Lappalainen, Aviv Regev, Kristin G. Ardlie, Nir Hacohen, Daniel G. Macarthur

Research output: Contribution to journalArticle

Abstract

X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals1,2. The extent to which XCI is shared between cells and tissues remains poorly characterized3,4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity6,7. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.

Original languageEnglish (US)
Pages (from-to)244-248
Number of pages5
JournalNature
Volume550
Issue number7675
DOIs
StatePublished - Oct 11 2017

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X Chromosome Inactivation
Genes
X Chromosome
Transcriptome
Sexism
Sex Characteristics

ASJC Scopus subject areas

  • General

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Tukiainen, T., Villani, A. C., Yen, A., Rivas, M. A., Marshall, J. L., Satija, R., ... Macarthur, D. G. (2017). Landscape of X chromosome inactivation across human tissues. Nature, 550(7675), 244-248. https://doi.org/10.1038/nature24265

Landscape of X chromosome inactivation across human tissues. / Tukiainen, Taru; Villani, Alexandra Chloé; Yen, Angela; Rivas, Manuel A.; Marshall, Jamie L.; Satija, Rahul; Aguirre, Matt; Gauthier, Laura; Fleharty, Mark; Kirby, Andrew; Cummings, Beryl B.; Castel, Stephane E.; Karczewski, Konrad J.; Aguet, François; Byrnes, Andrea; Lappalainen, Tuuli; Regev, Aviv; Ardlie, Kristin G.; Hacohen, Nir; Macarthur, Daniel G.

In: Nature, Vol. 550, No. 7675, 11.10.2017, p. 244-248.

Research output: Contribution to journalArticle

Tukiainen, T, Villani, AC, Yen, A, Rivas, MA, Marshall, JL, Satija, R, Aguirre, M, Gauthier, L, Fleharty, M, Kirby, A, Cummings, BB, Castel, SE, Karczewski, KJ, Aguet, F, Byrnes, A, Lappalainen, T, Regev, A, Ardlie, KG, Hacohen, N & Macarthur, DG 2017, 'Landscape of X chromosome inactivation across human tissues', Nature, vol. 550, no. 7675, pp. 244-248. https://doi.org/10.1038/nature24265
Tukiainen T, Villani AC, Yen A, Rivas MA, Marshall JL, Satija R et al. Landscape of X chromosome inactivation across human tissues. Nature. 2017 Oct 11;550(7675):244-248. https://doi.org/10.1038/nature24265
Tukiainen, Taru ; Villani, Alexandra Chloé ; Yen, Angela ; Rivas, Manuel A. ; Marshall, Jamie L. ; Satija, Rahul ; Aguirre, Matt ; Gauthier, Laura ; Fleharty, Mark ; Kirby, Andrew ; Cummings, Beryl B. ; Castel, Stephane E. ; Karczewski, Konrad J. ; Aguet, François ; Byrnes, Andrea ; Lappalainen, Tuuli ; Regev, Aviv ; Ardlie, Kristin G. ; Hacohen, Nir ; Macarthur, Daniel G. / Landscape of X chromosome inactivation across human tissues. In: Nature. 2017 ; Vol. 550, No. 7675. pp. 244-248.
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abstract = "X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals1,2. The extent to which XCI is shared between cells and tissues remains poorly characterized3,4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23{\%} of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity6,7. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.",
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AU - Satija, Rahul

AU - Aguirre, Matt

AU - Gauthier, Laura

AU - Fleharty, Mark

AU - Kirby, Andrew

AU - Cummings, Beryl B.

AU - Castel, Stephane E.

AU - Karczewski, Konrad J.

AU - Aguet, François

AU - Byrnes, Andrea

AU - Lappalainen, Tuuli

AU - Regev, Aviv

AU - Ardlie, Kristin G.

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N2 - X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of 'escape' from inactivation varying between genes and individuals1,2. The extent to which XCI is shared between cells and tissues remains poorly characterized3,4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity6,7. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.

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