The mRNA expression program of iPSC and fESC are strikingly similar42. Minor differences in mRNA and microRNA expression have been reported40, but removal of transgenes reduces the differences43. The Dlk1-Dio3 locus, whose expression correlates with capacity to generate “all-iPSC” mice44, is not differentially methylated and expressed in at least some iPSC lines that manifest epigenetic memory (our unpublished observations). Thus even the most stringently-defined iPSC might retain epigenetic memory. Importantly, differences between iPSC and fESC may not manifest until differentiation, when the specific loci that retain residual epigenetic marks are expressed, influencing cell fates. Methylation is but one molecular feature of “epigenetic memory” in iPSC. Faulty restoration of bivalent domains, which mark developmental loci with both active and repressive histone modifications 45, and loss of pioneer factors, which in fESC and iPSC occupy enhancers of genes expressed only in differentiated cells46, represent two other potential mechanisms.
