Ordered chromatin changes and human X chromosome reactivation by cell fusion-mediated pluripotent reprogramming

Irene Cantone, Hakan Bagci, Dirk Dormann, Gopuraja Dharmalingam, Tatyana Nesterova, Neil Brockdorff, Claire Rougeulle, Celine Vallot, Edith Heard, Ronan Chaligne, Matthias Merkenschlager and Amanda G. Fisher ()
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Irene Cantone: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine
Hakan Bagci: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine
Dirk Dormann: Microscopy Laboratory, MRC Clinical Sciences Centre, Imperial College School of Medicine
Gopuraja Dharmalingam: Bioinformatics and Computing facility, MRC Clinical Sciences Centre, Imperial College
Tatyana Nesterova: Developmental Epigenetics Group, University of Oxford
Neil Brockdorff: Developmental Epigenetics Group, University of Oxford
Claire Rougeulle: Epigenetics and Cell Fate, CNRS UMR7216, Université Paris Diderot
Celine Vallot: Epigenetics and Cell Fate, CNRS UMR7216, Université Paris Diderot
Edith Heard: Mammalian Developmental Epigenetics Group, Institut Curie
Ronan Chaligne: Mammalian Developmental Epigenetics Group, Institut Curie
Matthias Merkenschlager: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine
Amanda G. Fisher: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Erasure of epigenetic memory is required to convert somatic cells towards pluripotency. Reactivation of the inactive X chromosome (Xi) has been used to model epigenetic reprogramming in mouse, but human studies are hampered by Xi epigenetic instability and difficulties in tracking partially reprogrammed iPSCs. Here we use cell fusion to examine the earliest events in the reprogramming-induced Xi reactivation of human female fibroblasts. We show that a rapid and widespread loss of Xi-associated H3K27me3 and XIST occurs in fused cells and precedes the bi-allelic expression of selected Xi-genes by many heterokaryons (30–50%). After cell division, RNA-FISH and RNA-seq analyses confirm that Xi reactivation remains partial and that induction of human pluripotency-specific XACT transcripts is rare (1%). These data effectively separate pre- and post-mitotic events in reprogramming-induced Xi reactivation and reveal a complex hierarchy of epigenetic changes that are required to reactivate the genes on the human Xi chromosome.

Date: 2016
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DOI: 10.1038/ncomms12354

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