X Chromosome Inactivation and Epigenetic Responses to Cellular Reprogramming

Reprogramming somatic cells to derive induced pluripotent stem cells (iPSCs) has provided a new method to model disease and holds great promise for regenerative medicine. Although genetically identical to their donor somatic cells, iPSCs undergo substantial changes in the epigenetic landscape during reprogramming. One such epigenetic process, X chromosome inactivation (XCI), has recently been shown to vary widely in human female iPSCs and embryonic stem cells (ESCs). XCI is a form of dosage compensation whose chief regulator is the noncoding RNA Xist. In mouse iPSCs and ESCs, Xist expression and XCI strictly correlate with the pluripotent state, but no such correlation exists in humans. Lack of XIST expression in human cells is linked to reduced developmental potential and an altered transcriptional profile, including upregulation of genes associated with cancer, which has therefore led to concerns about the safety of pluripotent stem cells for use in regenerative medicine. In this review, we describe how different states of XIST expression define three classes of female human pluripotent stem cells and explore progress in discovering the reasons for these variations and how they might be countered.