4 years ago

Landscape of X chromosome inactivation across human tissues

Landscape of X chromosome inactivation across human tissues
Beryl B. Cummings, Matt Aguirre, Rahul Satija, Taru Tukiainen, Tuuli Lappalainen, Konrad J. Karczewski, Stephane E. Castel, Laura Gauthier, Angela Yen, Jamie L. Marshall, Alexandra-Chloé Villani, Andrea Byrnes, Andrew Kirby, Mark Fleharty, Nir Hacohen, Kristin G. Ardlie, Aviv Regev, Daniel G. MacArthur, François Aguet, Manuel A. Rivas
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 systems1 or to samples that have skewed XCI1, 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 tissues8 (Extended Data Fig. 1 and Supplementary Note). Others have used bias in DNA methylation3, 4, 9 or in gene expression5, 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 XCI11, 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 species7. 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.

Publisher URL: http://dx.doi.org/10.1038/nature24265

DOI: 10.1038/nature24265

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