Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation

Anna Sahakyan, Rachel Kim, Constantinos Chronis, Shan Sabri, Giancarlo Bonora, Thorold W. Theunissen, Edward Kuoy, Justin Langerman, Amander T. Clark, Rudolf Jaenisch, Kathrin Plath

Research output: Contribution to journalArticlepeer-review

162 Scopus citations


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.

Original languageEnglish
Pages (from-to)87-101
Number of pages15
JournalCell Stem Cell
Issue number1
StatePublished - Jan 5 2017


  • X chromosome
  • X chromosome dampening
  • X chromosome inactivation
  • XIST
  • embryonic stem cells
  • human development
  • human stem cells
  • lncRNA
  • naive pluripotency
  • pluripotent stem cells


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