title: Derivation of pre-X inactivation human embryonic stem cells under physiological oxygen concentrations.
abstract: The presence of two active X chromosomes (XaXa) is a hallmark of the ground state of pluripotency specific to murine embryonic stem cells (ESCs). Human ESCs (hESCs) invariably exhibit signs of X chromosome inactivation (XCI) and are considered developmentally more advanced than their murine counterparts. We describe the establishment of XaXa hESCs derived under physiological oxygen concentrations. Using these cell lines, we demonstrate that (1) differentiation of hESCs induces random XCI in a manner similar to murine ESCs, (2) chronic exposure to atmospheric oxygen is sufficient to induce irreversible XCI with minor changes of the transcriptome, (3) the Xa exhibits heavy methylation of the XIST promoter region, and (4) XCI is associated with demethylation and transcriptional activation of XIST along with H3K27-me3 deposition across the Xi. These findings indicate that the human blastocyst contains pre-X-inactivation cells and that this state is preserved in vitro through culture under physiological oxygen.
authors.affiliation: Whitehead Institute for Biomedical Sciences, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lengner
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Gimelbrant
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Erwin
authors.forename: Albert Wu
authors.initials: AW
authors.lastname: Cheng
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Guenther
authors.forename: G Grant
authors.initials: GG
authors.lastname: Welstead
authors.forename: Raaji
authors.initials: R
authors.lastname: Alagappan
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Frampton
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.forename: Julien
authors.initials: J
authors.lastname: Muffat
authors.forename: Sandro
authors.initials: S
authors.lastname: Santagata
authors.forename: Doug
authors.initials: D
authors.lastname: Powers
authors.forename: C Brent
authors.initials: CB
authors.lastname: Barrett
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.forename: Jeannie T
authors.initials: JT
authors.lastname: Lee
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.forename: Maisam
authors.initials: M
authors.lastname: Mitalipova
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D041321:Chromosomes, Human, X / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D007621:Karyotyping; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000378:metabolism; D049951:X Chromosome Inactivation
chemical_list: D006657:Histones; D010100:Oxygen