title: XACT Noncoding RNA Competes with XIST in the Control of X Chromosome Activity during Human Early Development.
abstract: Sex chromosome dosage compensation is essential in most metazoans, but the developmental timing and underlying mechanisms vary significantly, even among placental mammals. Here we identify human-specific mechanisms regulating X chromosome activity in early embryonic development. Single-cell RNA sequencing and imaging revealed co-activation and accumulation of the long noncoding RNAs (lncRNAs) XACT and XIST on active X chromosomes in both early human pre-implantation embryos and naive human embryonic stem cells. In these contexts, the XIST RNA adopts an unusual, highly dispersed organization, which may explain why it does not trigger X chromosome inactivation at this stage. Functional studies in transgenic mouse cells show that XACT influences XIST accumulation in cis. Our findings therefore suggest a mechanism involving antagonistic activity of XIST and XACT in controlling X chromosome activity in early human embryos, and they highlight the contribution of rapidly evolving lncRNAs to species-specific developmental mechanisms.
authors.affiliation: Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot, 75013 Paris, France. Electronic address: celine.vallot@univ-paris-diderot.fr.
authors.forename: Céline
authors.initials: C
authors.lastname: Vallot
authors.affiliation: Mammalian Developmental Epigenetics Group, Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, 75005 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France; Reproductive Biology Department, AP-HP, Bichat-Claude Bernard Hospital, 75018 Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Patrat
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Collier
authors.affiliation: Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot, 75013 Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Huret
authors.affiliation: Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot, 75013 Paris, France.
authors.forename: Miguel
authors.initials: M
authors.lastname: Casanova
authors.affiliation: Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot, 75013 Paris, France.
authors.forename: Tharvesh M
authors.initials: TM
authors.lastname: Liyakat Ali
authors.affiliation: Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot, 75013 Paris, France.
authors.forename: Matteo
authors.initials: M
authors.lastname: Tosolini
authors.affiliation: Université Paris-Sud, Clamart 92140, France; Unit of Reproductive Biology, AP-HP, Hôpital Antoine Béclère, Clamart 92141, France.
authors.forename: Nelly
authors.initials: N
authors.lastname: Frydman
authors.affiliation: Mammalian Developmental Epigenetics Group, Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, 75005 Paris, France.
authors.forename: Edith
authors.initials: E
authors.lastname: Heard
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rugg-Gunn
authors.affiliation: Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot, 75013 Paris, France. Electronic address: claire.rougeulle@univ-paris-diderot.fr.
authors.forename: Claire
authors.initials: C
authors.lastname: Rougeulle
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D041321:Chromosomes, Human, X / Q000235:genetics*; D019992:Databases as Topic; D047108:Embryonic Development / Q000235:genetics*; D000066449:Human Embryonic Stem Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D039904:Pluripotent Stem Cells / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis; D019076:Transgenes
chemical_list: D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C077885:XIST non-coding RNA; C000621435:long non-coding RNA XACT, human
keywords: XACT; XIST; dosage compensation; human X chromosome inactivation; long noncoding RNA; naive pluripotency; preimplantation development