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

Publication date: Available online 15 December 2016
Source:Cell Stem Cell
Author(s): Anna Sahakyan, Rachel Kim, Constantinos Chronis, Shan Sabri, Giancarlo Bonora, Thorold W. Theunissen, Edward Kuoy, Justin Langerman, Amander T. Clark, Rudolf Jaenisch, Kathrin Plath
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.

Graphical abstract

Teaser

Plath and colleagues study the epigenetic state of the X chromosomes in naive female hPSCs and discover that it closely, but not perfectly, resembles the X chromosome pattern of pre-implantation blastocysts. The naive state enables de novo X inactivation upon differentiation and thus can provide a model for studying X chromosome regulation in human cells.


http://ift.tt/2gHXmv2