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Derivation of Pre-X Inactivation Human Embryonic Stem Cells under Physiological Oxygen Concentrations$ v0 I) E7 S1 p+ G- J3 V, V8 {7 C
Christopher J. Lengner1, 11, Alexander A. Gimelbrant4, 5, 11, Jennifer A. Erwin6, 7, 8, Albert Wu Cheng1, 3, Matthew G. Guenther1, G. Grant Welstead1, Raaji Alagappan1, Garrett M. Frampton1, 2, Ping Xu1, Julien Muffat1, Sandro Santagata1, Doug Powers9, C. Brent Barrett10, Richard A. Young1, 2, Jeannie T. Lee6, 7, 8, Rudolf Jaenisch1, 2, , and Maisam Mitalipova1, , ' |" E" d0 j& }& V
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1 Whitehead Institute for Biomedical Sciences, 9 Cambridge Center, Cambridge, MA 02142, USA& X6 T! y( W! ~( i( v
2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
' r( j+ L$ ?! L3 M' R4 t3 Department of Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- A$ h3 ] o) j; ?3 @4 Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02115, USA2 K( ]7 I( K9 x2 S" M4 c" E5 A
5 Department of Pathology, Harvard Medical School, Boston, MA 02114, USA ?2 V7 V% q5 M0 F" X7 q1 K$ O
6 Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
, Z, N- @, k& ]7 I/ ?) [7 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA! ^, @: i( K' P, }
8 Howard Hughes Medical Institute
2 C4 Y5 ]* e% a9 Incept Biosystems, Ann Arbor, MI 48108, USA
6 t d3 v: }4 \" p* C- z10 Boston IVF, The Waltham Center, Waltham, MA 02451, USA* p5 f/ [, `7 [8 c; x$ L9 m+ w
% V, W- Y. k" o2 u8 QCorresponding author5 {. S6 X1 Z. W# y G: c
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Corresponding author
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& H0 m+ u- p/ R11 These authors contributed equally to this work
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3 V& x" r0 O, UGraphical Abstract
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2 A5 z/ _% Y7 ]. i+ A( C( P! eHighlights- X) b$ x, i6 w2 A
► Conventional human ESCs (hESCs) have undergone X chromosome inactivation (XiXa) ► hESCs with two active X chromosomes (XaXa) can be isolated in 5% oxygen ► Oxidative and cellular stress induces irreversible epigenetic changes in hESCs ► Human blastocysts likely contain cells with two active X chromosomes (XaXa)
% ] N# ^- R2 ]' p: E2 lSummary- E; ^$ O$ h, T* H
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) b( s+ L# G- C
http://www.cell.com/abstract/S0092-8674(10)00384-3 |
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发表于 2010-6-30 16:16
