Erosion of X Chromosome Inactivation in Human Pluripotent Cells Initiates with XACT Coating and Depends on a Specific Heterochromatin Landscape.
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.
Epigenetics and Cell Fate, Université Paris Diderot, Sorbonne Paris Cité, 75013 Paris, France; CNRS, UMR7216 Epigenetics and Cell Fate, 75013 Paris, France.
Céline
C
Vallot
Epigenetics and Cell Fate, Université Paris Diderot, Sorbonne Paris Cité, 75013 Paris, France; CNRS, UMR7216 Epigenetics and Cell Fate, 75013 Paris, France.
Jean-François
JF
Ouimette
Epigenetics and Cell Fate, Université Paris Diderot, Sorbonne Paris Cité, 75013 Paris, France; CNRS, UMR7216 Epigenetics and Cell Fate, 75013 Paris, France.
Mélanie
M
Makhlouf
ESTeam Paris Sud, INSERM U935, Université Paris Sud 11, AP-HP, Villejuif 94802, France.
Olivier
O
Féraud
Epigenetics and Cell Fate, Université Paris Diderot, Sorbonne Paris Cité, 75013 Paris, France; CNRS, UMR7216 Epigenetics and Cell Fate, 75013 Paris, France.
Julien
J
Pontis
INSERM/UEVE UMR 861, ISTEM, AFM, 91030 Evry Cedex, France.
Julien
J
Côme
INSERM/UEVE UMR 861, ISTEM, AFM, 91030 Evry Cedex, France.
Cécile
C
Martinat
ESTeam Paris Sud, INSERM U935, Université Paris Sud 11, AP-HP, Villejuif 94802, France.
Annelise
A
Bennaceur-Griscelli
Stem Cell and Systems Genomics Institutes, University of Connecticut, Farmington, CT 06030, USA.
Marc
M
Lalande
Epigenetics and Cell Fate, Université Paris Diderot, Sorbonne Paris Cité, 75013 Paris, France; CNRS, UMR7216 Epigenetics and Cell Fate, 75013 Paris, France. Electronic address: claire.rougeulle@univ-paris-diderot.fr.
Claire
C
Rougeulle
D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D041321:Chromosomes, Human, X / Q000235:genetics*; D063185:Epigenetic Repression; D006570:Heterochromatin / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039904:Pluripotent Stem Cells / Q000502:physiology*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D049951:X Chromosome Inactivation
D006570:Heterochromatin; D006657:Histones; D062085:RNA, Long Noncoding; C077885:XIST non-coding RNA