The co-regulation of pluripotency and enhanced maintenance of genetic integrity at the genomic level
One important but poorly characterized aspect of stem cells is their ability to maintain genetic integrity while pluripotent, when induced to differentiate, and/or when derived from differentiated cells by reprogramming. In this study we test the hypothesis that pluripotency and enhanced genetic integrity are mechanistically linked at the genomic level. Using both in silico and in vitro methodologies, we examined the expression of genes related to genetic integrity maintenance (DNA repair and cell death) in pluripotent and somatic cells, regulation of the genes by pluripotency transcription factors, and performed direct mutagenesis to determine the extent to which pluripotent cells can mitigate induced point-mutation genomic damage. We found that genes responsible for DNA repair and cell death mechanisms show overall up-regulation in pluripotent cell types and are directly and indirectly regulated by pluripotency transcription factors at the genomic level. We observed that pluripotent cells showed substantially lower increases in incidence of point mutations when exposed to a mutagenic agent compared to differentiated cells. Taken together, our data support our hypothesis that enhanced maintenance of genetic integrity is mechanistically linked to the epigenetic state of pluripotency – by the expression of pluripotency factors, at the genomic level. In addition, these findings demonstrate how a small number of key pluripotency factors can regulate large numbers of downstream genes in a pathway-specific manner.