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

Cell Stem Cell
Authors
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
Journal
Cell Stem Cell
Volume
20
Issue
1
Pages
87-101
Date Published
2017 Jan 05
ISSN
1875-9777
DOI
10.1016/j.stem.2016.10.006
PubMed ID
27989770
PubMed Central ID
PMC5218861
Links
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