The Path to Pluripotency: Dissecting the Reprogrammed Cells

Source: Mikkelsen et al (2008). Dissecting direct reprogramming through integrative genomic analysis. Nature 454: 49-55.

I am not really familiar with this field but I found this paper interesting in the sense that it employs whole-genome methods to tackle a specific and important problem. Human and mouse cells can be transformed back into a pluripotent stage (termed iPS cells) through re-expression of specific transcription factors. However, the success rate of this method is low and the molecular characteristics of this transition is poorly understood.

The first step in reprogramming involves the ectopic expressin of Oct4, Sox2, Klf4 and c-Myc transcription factors. De-differentitation and proliferation of the cells is marked by a decrease in the expression of tissue-specific genes (in this case Snai1 and Snai2) and an increase in DNA replication and cell-cycle progression genes. A parallel boost in the expression of anti-proliferative genes suggests that the mechanism to inhibit uncontrolled prliferation is intact.

Reprogrammed iPS cells, by large, share the expression of key genes with the embryonic stem cells. In this study, however, the authors have extended this similarity to the chromatin structure as well. Much of the details, in this paper, come from studying the partially reprogrammed cells. For example, MCV8, a cell line achieved as a byproduct of an unsuccessful reprogramming, can give rise to both iPS and differentiated cells with an inherent stochasticity involved.

Based on their observations, the authors argue that the cells fail to reprogram because:

1. The cells may induce anti-proliferative genes in response to proliferative stress;
2. They may inappropriately activate or fail to repress endogenous or ectopic transcription factors, and become ‘trapped’ in differentiated states;
3. They may fail to reactivate hypermethylated pluripotency genes.

The bottom line is the fact that reprogramming can be facilitated through another layer of gene regulation (besides the initial four transcription factors).