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Proc Natl Acad Sci U S A. 2018 Dec 18;115(51):13015-13020. doi: 10.1073/pnas.1806811115. Epub 2018 Dec 3.

Extensive cellular heterogeneity of X inactivation revealed by single-cell allele-specific expression in human fibroblasts.

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Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, CH, Switzerland.
Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, CH, Switzerland;
Service of Endocrinology, Diabetology, and Metabolism, University Hospitals of Lausanne, 1011 Lausanne, CH, Switzerland.
Faculty of Biology and Medicine, University of Lausanne, 1015 Lausanne, CH, Switzerland.
University Hospitals of Geneva, 1205 Geneva, CH, Switzerland.
iGE3 Institute of Genetics and Genomics, University of Geneva, 1211 Geneva, CH, Switzerland.


X-chromosome inactivation (XCI) provides a dosage compensation mechanism where, in each female cell, one of the two X chromosomes is randomly silenced. However, some genes on the inactive X chromosome and outside the pseudoautosomal regions escape from XCI and are expressed from both alleles (escapees). We investigated XCI at single-cell resolution combining deep single-cell RNA sequencing with whole-genome sequencing to examine allelic-specific expression in 935 primary fibroblast and 48 lymphoblastoid single cells from five female individuals. In this framework we integrated an original method to identify and exclude doublets of cells. In fibroblast cells, we have identified 55 genes as escapees including five undescribed escapee genes. Moreover, we observed that all genes exhibit a variable propensity to escape XCI in each cell and cell type and that each cell displays a distinct expression profile of the escapee genes. A metric, the Inactivation Score-defined as the mean of the allelic expression profiles of the escapees per cell-enables us to discover a heterogeneous and continuous degree of cellular XCI with extremes represented by "inactive" cells, i.e., cells exclusively expressing the escaping genes from the active X chromosome and "escaping" cells expressing the escapees from both alleles. We found that this effect is associated with cell-cycle phases and, independently, with the XIST expression level, which is higher in the quiescent phase (G0). Single-cell allele-specific expression is a powerful tool to identify novel escapees in different tissues and provide evidence of an unexpected cellular heterogeneity of XCI.


X inactivation; XIST; cell cycle; cell heterogeneity; single-cell transcriptomics

[Available on 2019-06-18]

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