How does reprogramming to pluripotency affect genomic imprinting?

Human induced Pluripotent Stem Cells (hiPSCs) have the capacity to generate a wide range of somatic cells, thus representing an ideal tool for regenerative medicine. Patient-derived hiPSCs are also used for in vitro disease modeling and drug screenings. Several studies focused on the identification of DNA mutations generated, or selected, during the derivation of hiPSCs, some of which are known to drive cancer formation. Avoiding such stable genomic aberrations is paramount for successful use of hiPSCs, but it is equally important to ensure that their epigenetic information is correct, given the critical role of epigenetics in transcriptional regulation and its involvement in a plethora of pathologic conditions. In this review we will focus on genomic imprinting, a prototypical epigenetic mechanism whereby a gene is expressed in a parent-of-origin specific manner, thanks to the differential methylation of specific DNA sequences. Conventional hiPSCs are thought to be in a pluripotent state primed for differentiation. They display a hypermethylated genome with an unexpected loss of DNA methylation at imprinted loci. Several groups recently reported the generation of hiPSCs in a more primitive developmental stage, called naïve pluripotency. Naïve hiPSCs share several features with early human embryos, such as a global genome hypomethylation, which is also accompanied by a widespread loss of DNA methylation at imprinted loci. Given that loss of imprinting has been observed in genetic developmental disorders as well as in a wide range of cancers, it is fundamental to make sure that hiPSCs do not show such epigenetic aberrations. We will discuss what specific imprinted genes, associated with human pathologies, have been found commonly misregulated in hiPSCs and suggest strategies to effectively detect and avoid such undesirable epigenetic abnormalities.