By studying genome-wide DNA methylation and gene expression profiles in a large and diverse collection of pluripotent and somatic samples, we have discovered that pluripotent cells differ from somatic cells at sites in the genome that are generally considered to be epigenetically stable: the inactivated X chromosome in female cells and imprinted loci. Among pluripotent cultures, there was a large degree of variation at these sites, and their methylation status was not changed with differentiation. These epigenetic instabilities merit a degree of caution in the interpretation of X-linked hPSC-based disease models, and indicate that hPSC derivatives destined for clinical use should be examined for aberrations in imprinting and XCI. Therefore, identification of specific culture conditions or small molecules that promote the stability of genomic imprints and XCI over long-term culture would be of great value to the stem cell community.
