Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an ‘epigenetic memory’ of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment. Induced pluripotent stem (iPS) cells are produced by reprogramming differentiated adult cells using a cocktail of transcription factors. They share many properties that are characteristic of embryonic stem (ES) cells generated by somatic-cell nuclear transfer (SCNT), and of ES cells from naturally fertilized embryos. The three cell types are not identical, however, and an interesting difference has now been discovered: iPS cells retain an 'epigenetic memory' of the donor tissue from which they derive, whereas SCNT-based reprogramming resets the DNA-methylation state of adult cells so it is closer to the ES cell-like state. In a separate study, Ji et al. examine the role of specific DNA methylation marks in the developmental progression of particular cell lineages. They present a genome-wide DNA-methylation analysis of haematopoietic cell populations that reveals remarkable epigenetic plasticity. Changes in DNA methylation emerge as perhaps a principal factor directing cell-fate choices such as commitment to myeloid or lymphoid development. Pluripotent stem cells can be generated in the laboratory through somatic cell nuclear transfer (generating nuclear transfer embryonic stem cells, ntESCs) or transcription-factor-based reprogramming (producing induced pluripotent stem cells, iPSCs). These methods reset the methylation signature of the genome — but to what extent? Here it is found that mouse iPSCs 'remember' the methylation status of their tissue of origin, but the methylation of ntESCs is more similar to that of naturally produced ES cells.

Epigenetic memory in induced pluripotent stem cells