Panova Alexandra V, Bogomazova Alexandra N, Lagarkova Maria A, Kiselev Sergey L
Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119991, Russia.
Scientific-Research Institute of Physical-Chemical Medicine, Moscow 119435, Russia.
Oncotarget. 2018 May 18;9(38):25136-25147. doi: 10.18632/oncotarget.25353.
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 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.
女性人类多能干细胞（PSCs）具有可变的X染色体失活（XCI）状态。两条X染色体中的一条可能处于失活状态（Xi），或者显示出一些活跃状态标记。PSCs的长期培养可能导致XCI的侵蚀和部分X染色体重新激活。XCI状态的这种异质性和不稳定性可能会阻碍人类女性PSCs在治疗或疾病建模中的应用。我们试图通过将人类胚胎干细胞（hESCs）重编程为原始状态来解决XCI的异质性问题。我们在原始培养条件下培养了五条hESC系。PSCs获得了原始细胞特征，尽管这些变化并非在所有hESC系中都是一致的。向原始状态的转变伴随着某些基因表达的丧失、Xi H3K27me3富集的丧失以及Xi复制与活跃X染色体同步的转变，但有两个区域除外。在两条hESC系的所有细胞中都观察到了这种Xi重新激活的模式。然而，这些细胞在自发分化时无法经历经典的XCI。我们得出结论，原始培养条件无法解决女性人类ESC系中XCI状态的变异性问题，并建立了一种不可逆的部分X染色体重新激活的异质模式。
