Oncotarget

Research Papers:

Epigenetic reprogramming by naïve conditions establishes an irreversible state of partial X chromosome reactivation in female stem cells

Alexandra V. Panova, Alexandra N. Bogomazova, Maria A. Lagarkova and Sergey L. Kiselev _

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Oncotarget. 2018; 9:25136-25147. https://doi.org/10.18632/oncotarget.25353

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Abstract

Alexandra V. Panova1, Alexandra N. Bogomazova1, Maria A. Lagarkova1,2 and Sergey L. Kiselev1

1Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119991, Russia

2Scientific-Research Institute of Physical-Chemical Medicine, Moscow 119435, Russia

Correspondence to:

Sergey L. Kiselev, email: kiselev@vigg.ru

Keywords: X chromosome inactivation; naïve; reprogramming; pluripotency; 5-hydroxymethylcytosine

Received: March 22, 2018     Accepted: April 24, 2018     Published: May 18, 2018

ABSTRACT

Female human pluripotent stem cells (PSCs) have variable X-chromosome inactivation (XCI) status. One of the X chromosomes may either be inactive (Xi) or display some active state markers. Long-term cultivation of PSCs may lead to an erosion of XCI and partial X reactivation. Such heterogeneity and instability of XCI status might hamper the application of human female PSCs for therapy or disease modeling. We attempted to address XCI heterogeneity by reprogramming human embryonic stem cells (hESCs) to the naïve state. We propagated five hESC lines under naïve culture conditions. PSCs acquired naïve cells characteristics although these changes were not uniform for all of the hESC lines. Transition to the naïve state was accompanied by a loss of XIST expression, loss of Xi H3K27me3 enrichment and a switch in Xi replication synchronously with active X, except for two regions. This pattern of Xi reactivation was observed in all cells in two hESC lines. However, these cells were unable to undergo classical XCI upon spontaneous differentiation. We conclude that naïve culture conditions do not resolve the variability in XCI status in female human ESC lines and establish an irreversible heterogeneous pattern of partial X reactivation.


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