Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation.
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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. |
Year of Publication | 2017
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Journal | Cell Stem Cell
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Volume | 20
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Issue | 1
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Pages | 87-101
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Date Published | 2017 Jan 05
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ISSN | 1875-9777
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DOI | 10.1016/j.stem.2016.10.006
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PubMed ID | 27989770
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PubMed Central ID | PMC5218861
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Grant list | R01 MH104610 / MH / NIMH NIH HHS / United States
F31 GM115122 / GM / NIGMS NIH HHS / United States
R01 HD079546 / HD / NICHD NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
P01 GM099134 / GM / NIGMS NIH HHS / United States
R01 CA084198 / CA / NCI NIH HHS / United States
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