X Chromosome of Female Cells Shows Dynamic Changes in Status during Human Somatic Cell Reprogramming

• The X chromosome state changes dynamically during human somatic cell reprogramming
• Ectopic reprogramming factors transiently activate the inactive X chromosome
• Nascent iPSC colonies carry an inactive X chromosome
• Class I and class III iPSCs arise from nascent iPSCs

SummaryInduced pluripotent stem cells (iPSCs) acquire embryonic stem cell (ESC)-like epigenetic states, including the X chromosome. Previous studies reported that human iPSCs retain the inactive X chromosome of parental cells, or acquire two active X chromosomes through reprogramming. Most studies investigated the X chromosome states in established human iPSC clones after completion of reprogramming. Thus, it is still not fully understood when and how the X chromosome reactivation occurs during reprogramming. Here, we report a dynamic change in the X chromosome state throughout reprogramming, with an initial robust reactivation of the inactive X chromosome followed by an inactivation upon generation of nascent iPSC clones. iPSCs with two active X chromosomes or an eroded X chromosome arise in passaging iPSCs. These data provide important insights into the plasticity of the X chromosome of human female iPSCs and will be crucial for the future application of such cells in cell therapy and X-linked disease modeling.

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