Erosion of X Chromosome Inactivation in Human Pluripotent Cells Initiates with XACT Coating and Depends on a Specific Heterochromatin Landscape

• Published in: Cell stem cell 2015-05, Vol.16 (5), p.533-546
• Main Authors: Vallot, Céline, Ouimette, Jean-François, Makhlouf, Mélanie, Féraud, Olivier, Pontis, Julien, Côme, Julien, Martinat, Cécile, Bennaceur-Griscelli, Annelise, Lalande, Marc, Rougeulle, Claire
• Format: Article
• Language: English
• Subjects: Cell Line; Chromatin Assembly and Disassembly; Chromosomes, Human, X - genetics; Epigenetic Repression; Heterochromatin - metabolism; Histones - genetics; Histones - metabolism; Humans; Life Sciences; Pluripotent Stem Cells - physiology; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Transcription, Genetic; X Chromosome Inactivation
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2015.03.016

Human pluripotent stem cells (hPSCs) display extensive epigenetic instability, particularly on the X chromosome. In this study, we show that, in hPSCs, the inactive X chromosome has a specific heterochromatin landscape that predisposes it to erosion of X chromosome inactivation (XCI), a process that occurs spontaneously in hPSCs. Heterochromatin remodeling and gene reactivation occur in a non-random fashion and are confined to specific H3K27me3-enriched domains, leaving H3K9me3-marked regions unaffected. Using single-cell monitoring of XCI erosion, we show that this instability only occurs in pluripotent cells. We also provide evidence that loss of XIST expression is not the primary cause of XCI instability and that gene reactivation from the inactive X (Xi) precedes loss of XIST coating. Notably, expression and coating by the long non-coding RNA XACT are early events in XCI erosion and, therefore, may play a role in mediating this process. [Display omitted] •The inactive X chromosome in hPSCs has a specific partitioned chromatin structure•Erosion of X inactivation occurs in a subset of heterochromatin domains•X inactivation instability is restricted to pluripotent cells•Re-expression of XACT is an early step in the erosion of X inactivation Rougeulle and colleagues show that XCI erosion in human pluripotent cells is related to a pluripotency-specific epigenomic landscape on the inactive X chromosome, and that coating by the XACT lncRNA and gene reactivation precedes loss of XIST expression during this process.