Molecular Basis of Cell Reprogramming into iPSCs with Exogenous Transcription Factors.

A striking discovery in recent decades concerning the transcription factor (TF)-dependent process was the production of induced pluripotent stem cell (iPSCs) from fibroblasts by the exogenous expression of the TF cocktail containing Oct3/4 (Pou5f1), Sox2, Klf4, and Myc, collectively called OSKM. How fibroblast cells can be remodeled into embryonic stem cell (ESC)-like iPSCs despite high epigenetic barriers has opened a new essential avenue to understanding the action of TFs in developmental regulation. Two forerunning investigations preceded the iPSC phenomenon: exogenous TF-mediated cell remodeling driven by the action of MyoD, and the "pioneer TF" action to preopen chromatin, allowing multiple TFs to access enhancer sequences. The process of remodeling somatic cells into iPSCs has been broken down into multiple subprocesses: the initial attack of OSKM on closed chromatin, sequential changes in cytosine modification, enhancer usage, and gene silencing and activation. Notably, the OSKM TFs change their genomic binding sites extensively. The analyses are still at the descriptive stage, but currently available information is discussed in this chapter.