Genomic instability in iPS: time for a break

Abstract

The discovery of a simple protocol capable of generating pluripotent stem cells from terminally differentiated cells has been one of the most promising breakthroughs in recent biomedical research. Since their discovery, manuscripts characterizing properties of induced Pluripotent Stem (iPS) have flooded the literature. Among others, the analysis of the transcriptome and epigenome of iPS is now a recurrent theme that is helping to understand the molecular mechanisms behind reprogramming. Recent works have revealed that transcriptional and epigenetic reprogramming is often incomplete, which has raised some concerns on the nature of iPS. Inevitably, now the genome itself of iPS has been scrutinized; and the reports come with an unexpected twist: the presence of mutations in the genome of iPS.

Figure 1

The roads to genomic instability in iPS. The figure illustrates the different mechanisms that have been postulated as being the drivers of genomic instability on iPS. (1) In an analogy to the oncogene-induced DNA damage theory, it is possible that reprogramming factors (some of which are actually bona fide proto-oncogenes) fuel ‘reprogramming-induced DNA damage’. (2) In contrast, it is possible that the observed mutations (particularly for the case of point coding mutations) might be already present in a small fraction of the differentiated cells. In this model, these mutations would be selected for, rather than generated, during reprogramming. (3) Finally, pluripotent genomes (both iPS and ES) might be intrinsically unstable, (4) a phenomenon that would be further influenced by time in culture and in vitro manipulation. We would like to suggest that this intrinsic instability might be influenced by the ‘open’ chromatin configuration of pluripotent cells, and which might have been behind the selection of pluripotency as a very transient state in multicellular organisms.