Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation
Authors: Amander T Clark
Anna Sahakyan
Thorold W Theunissen
Justin Langerman
Rachel Kim
Edward Kuoy
Kathrin Plath
Rudolf Jaenisch
Shan Sabri
Constantinos Chronis
Giancarlo Bonora
Journal: Cell stem cell (2017)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: X chromosome; X chromosome dampening; X chromosome inactivation; XIST; embryonic stem cells
Affiliations: Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA., Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA., Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA., Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA., Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA., Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA., Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA., Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: .

Abstract:  Naive human embryonic stem cells (hESCs) can be derived from primed hESCs or directly from blastocysts, but their X chromosome state has remained unresolved. Here, we show that the inactive X chromosome (Xi) of primed hESCs was reactivated in naive culture conditions. Like cells of the blastocyst, the resulting naive cells contained two active X chromosomes with XIST expression and chromosome-wide transcriptional dampening and initiated XIST-mediated X inactivation upon differentiation. Both establishment of and exit from the naive state (differentiation) happened via an XIST-negative XaXa intermediate. Together, these findings identify a cell culture system for functionally exploring the two X chromosome dosage compensation processes in early human development: X dampening and X inactivation. However, remaining differences between naive hESCs and embryonic cells related to mono-allelic XIST expression and non-random X inactivation highlight the need for further culture improvement. As the naive state resets Xi abnormalities seen in primed hESCs, it may provide cells better suited for downstream applications. 

Retracted: No

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 #6 The low mapping ratios are due to abundant expression of retrotransposon in the Naive hESCs. See Yin, Ying, Liquan Zhou, and Shuiqiao Yuan.  Enigma of retrotransposon biology in mammalian early embryos and embryonic stem cells. Stem cells international 2018 (2018). , 
 The major conclusion about X chromosome reactivation and dampening have been debunked by this recent elegant work. https: www.cell.com stem-cell-reports pdf S2213-6711(20)30117-X.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS221367112030117X%3Fshowall%3Dtrue Stem Cell Reports . 2020 May 12;14(5):745-754. doi: 10.1016 j.stemcr.2020.03.027. Epub 2020 Apr 30. Single-Cell Analysis Reveals Partial Reactivation of X Chromosome Instead of Chromosome-wide Dampening in Naive Human Pluripotent Stem Cells Susmita Mandal 1, Deepshikha Chandel 1, Harman Kaur 1, Sudeshna Majumdar 1, Maniteja Arava 1, Srimonta Gayen 2 ,