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 (+247 others)
2017 Nature  
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 individuals 1,2 . The extent to which XCI is shared between cells
more » ... d tissues remains poorly characterized 3,4 , as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression 5 and phenotypic traits 6 . 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 diversity 6,7 . 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. Mammalian female tissues consist of two mixed cell populations, each with either the maternally or paternally inherited X chromosome marked for inactivation. To overcome this heterogeneity, assessments of human XCI have often been confined to the use of artificial cell systems 1 or to samples that have skewed XCI 1,2 , that is, preferential inactivation of one of the two X chromosomes; this is common in clonal cell lines but rare in karyotypically normal, primary human tissues 8 (Extended Data Fig. 1and Supplementary Note). Others have used bias in DNA methylation 3,4,9 or in gene expression 5,10 between males and females as a proxy for XCI status. Surveys of XCI are powerful in engineered model organisms, for example, mouse models with completely skewed XCI 11 , but the degree to which these discoveries are generalizable to human XCI remains unclear given marked differences in XCI initiation and the extent of escape across species 7 . Here we describe a systematic survey of the landscape of human XCI using three complementary RNA sequencing (RNA-seq)-based approaches (Fig. 1 ) that together enable the assessment of XCI from individual cells to population level across a diverse range of human tissues.
doi:10.1038/nature24265 pmid:29022598 pmcid:PMC5685192 fatcat:bkdhcafyzba5bfhisp5adbb5oq