X chromosome reactivation dynamics reveal stages of reprogramming to pluripotency.

Cell
Authors
Keywords
Abstract

Reprogramming to iPSCs resets the epigenome of somatic cells, including the reversal of X chromosome inactivation. We sought to gain insight into the steps underlying the reprogramming process by examining the means by which reprogramming leads to X chromosome reactivation (XCR). Analyzing single cells in situ, we found that hallmarks of the inactive X (Xi) change sequentially, providing a direct readout of reprogramming progression. Several epigenetic changes on the Xi occur in the inverse order of developmental X inactivation, whereas others are uncoupled from this sequence. Among the latter, DNA methylation has an extraordinary long persistence on the Xi during reprogramming, and, like Xist expression, is erased only after pluripotency genes are activated. Mechanistically, XCR requires both DNA demethylation and Xist silencing, ensuring that only cells undergoing faithful reprogramming initiate XCR. Our study defines the epigenetic state of multiple sequential reprogramming intermediates and establishes a paradigm for studying cell fate transitions during reprogramming.

Year of Publication
2014
Journal
Cell
Volume
159
Issue
7
Pages
1681-97
Date Published
2014 Dec 18
ISSN
1097-4172
URL
DOI
10.1016/j.cell.2014.11.040
PubMed ID
25525883
PubMed Central ID
PMC4282187
Links
Grant list
GM007185 / GM / NIGMS NIH HHS / United States
P01 GM099117 / GM / NIGMS NIH HHS / United States
DP2 OD001686 / OD / NIH HHS / United States
R25 GM055052 / GM / NIGMS NIH HHS / United States
P01 GM099134 / GM / NIGMS NIH HHS / United States
P01GM099117 / GM / NIGMS NIH HHS / United States
T32 GM007185 / GM / NIGMS NIH HHS / United States
T32 AI060567 / AI / NIAID NIH HHS / United States
R25GM055052 / GM / NIGMS NIH HHS / United States
P01 GM081621 / GM / NIGMS NIH HHS / United States
5T32AI060567-07 / AI / NIAID NIH HHS / United States