Epigenetics of induced pluripotency, the seven-headed dragon

Abstract

Induction of pluripotency from somatic cells by exogenous transcription factors is made possible by a variety of epigenetic changes that take place during the reprogramming process. The derivation of fully reprogrammed induced pluripotent stem (iPS) cells is achieved through establishment of embryonic stem cell (ESC)-like epigenetic architecture permitting the reactivation of key endogenous pluripotency-related genes, establishment of appropriate bivalent chromatin domains and DNA hypomethylation of genomic heterochromatic regions. Restructuring of the epigenetic landscape, however, is a very inefficient process and the vast majority of the induced cells fail to complete the reprogramming process. Optimal ESC-like epigenetic reorganization is necessary for all reliable downstream uses of iPS cells, including in vitro modeling of disease and clinical applications. Here, we discuss the key advancements in the understanding of dynamic epigenetic changes taking place over the course of the reprogramming process and how aberrant epigenetic remodeling may impact downstream applications of iPS cell technology.

Figure 1

Dynamic epigenetic changes characterize the gradual reprogramming process. Four stages of reprogramming are illustrated as differentiated starting cell type (that is, murine embryonic fibroblasts), intermediate, partially reprogrammed induced pluripotent stem (iPS) cells and fully reprogrammed iPS cells. Activation of pluripotency-associated loci results in iPS cells' ability to stably self-renew and precisely control the embryonic stem cell (ESC)-like transcriptional profile. Proper histone methylation levels at the right genomic regions establishes bivalent chromatin domains not necessarily involved in the induction to pluripotency but required for proper differentiation capacity of iPS cells. DNA methylation levels are reduced in female ESC and iPS cell lines at heterochromatic satellite repeat elements. The functional significance of DNA hypomethylation is currently not understood but could be a reflection of the reactivated inactive-X chromosome. On the other hand, DNA methylation marks of imprinted genes remain protected from demethylation and are comparable to the levels in the starting cell type. Finally, it is not known whether extensive epigenetic changes accompanying the reprogramming process result in physical structural changes to the chromatin fibers themselves.