Somatic cell reprogramming requires cells to undergo dramatic changes in gene expression, DNA methylation, and chromatin structure. While current reprogramming approaches give rise to induced pluripotent stem cells (iPSCs) that largely reflect embryonic stem cells (ESCs), persistent transcriptome differences and the perdurance of somatic ‘epigenetic memory’ hinder the safe and efficacious use of these cells. Therefore, understanding the molecular mechanisms by which a pluripotent-specific transcriptome and epigenome are established in iPSCs is essential for overcoming current barriers in reprogramming.
Our lab has recently identified the XPC DNA repair complex as an important component in the pluripotency regulatory network (Fong et al., 2011). The XPC complex is recruited to regulatory elements bound by OCT4/SOX2 and is required for robust OCT4/SOX2-dependent transcription. Moreover, the XPC complex has also been shown to stimulate the activity of thymine DNA glycosylase (TDG), a major player in active DNA demethylation, in vitro (Shimizu et al., 2003). This raises the possibility that XPC may play a role in coupling efficient DNA demethylation and robust ESC-specific transcription through the recruitment of TDG activity to sites bound by XPC and core ESC transcription factors. We are currently investigating the influence of XPC on the methylation landscape and its affect on reprogramming.