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.
Original language | English |
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Pages (from-to) | 87-101 |
Number of pages | 15 |
Journal | Cell Stem Cell |
Volume | 20 |
Issue number | 1 |
DOIs | |
State | Published - Jan 5 2017 |
Keywords
- X chromosome
- X chromosome dampening
- X chromosome inactivation
- XIST
- embryonic stem cells
- human development
- human stem cells
- lncRNA
- naive pluripotency
- pluripotent stem cells