A remarkable paper in the journal Nature by Claudia Doege and others (Nature 488, 652-655 (2012)) has revealed the mechanism by which cells are reprogrammed to induced pluripotent stem cells (iPSCs).
Fully differentiated cells have those genes that induce pluripotency (that is, the ability to form any cell type in the adult body) completely shut off (see Takahashi and Yamanaka, Cell 126, 663-676 (2006)). However, if four different genes are introduced into these differentiated cells, namely Oct4, Sox2, c-Myc and Klf4, then the differentiated cell de-differentiates into an iPSC. However, how these genes do this has been rather elusive. However the Doege et al. paper has elucidated our understanding of this process.
To begin, we must understand that gene expression is jointly controlled by two classes of proteins and these include transcription factors, which bind to targets in DNA and activate DNA, and epigenetic regulators that alter the proteins that package DNA (histones). Doege and others have identified two epigenetic regulators called Parp1 and Tet2 that stimulate the expression of the dormant pluripotency genes in differentiated cells that convert them into iPSCs.
What do these proteins do? Parp1 and Tet2 induce the removal of a chemical tag (H3K27me3, for those who are interested) from those histones associated with pluripotency genes and induce the addition of a different chemical tag (H3K4me2, again for the interested). The first chemical tag on the histones shut down gene expression, but the second type of chemical tag induce gene expression.
Doege and his colleagues showed that these epigenetic changes occur before increased expression is detected in two pluripotency genes (Nanog and Esrrb). These epigenetic changes are highly correlated with the binding of the transcription factor Oct4 (also known as POU5F1). Oct4, you see, activates the expression of Parp1, and after the histones are properly modified, Oct4 can bind to the promoter of these genes and activate their expression.
This report shows, for the first time, that epigenetic regulators are equally as important as transcription factors in the status switch from differentiated state to iPSC. According to the accompanying summary of Doege’s article by Kyle Loh and Bing Lim, “reprogramming transcription factors liaise with endogenous epigenetic regulators to execute reprogramming.”
Source – Loh and Lim, Epigenetics: Actors in the cell reprogramming drama. Nature 488,599–600 (30 August 2012); doi:10.1038/488599a
Loh and Lim point out that this work also raises new questions. For example, how do Parp1 and Tet2 specifically activate these pluripotency genes rather than affecting the genome globally? Are there cell-type specific epigenetic regulators? Does this mechanism work for other cell types as well? Does this explain why some cell types become iPSCs so much more efficiently than others? Doege et al. have written an incredible paper that blasts open the door of on our understanding of iPSC formation. This should provide new insights into reprogramming in general.