UC Berkeley

Embryonic stem cells (ESCs), like all tissues, largely rely on precise transcriptional and epigenetic regulation for proper cell specification and differentiation. General transcription factors, transcriptional regulators, coactivators, and chromatin remodelers are often coordinated and expressed in a cell-type specific manner to ensure the integrity of this gene expression network. However, how ESCs are able to tightly regulate gene expression and remain highly malleable to external developmental cues is still an open biological question. The XPC DNA repair complex was recently identified as one of a set of critical stem cell coactivators (SCC) involved in driving robust OCT4/SOX2-dependent expression of pluripotent genes in ESCs. This dissertation will focus on the molecular mechanisms of the XPC complex and other SCCs in controlling cell identity and fate in pluripotent stem cells.

Chapter 1 will provide an introduction to the transcriptional and epigenetic regulation in pluripotent stem cells. Specifically, it will highlight the core transcriptional network, the mechanisms of reprogramming, and barriers to gene expression (e.g. DNA methylation). Chapter 2 will describe a novel role of the XPC DNA repair complex in regulating DNA methylation in both somatic and pluripotent cells, in part through regulating the activity of thymine DNA glycosylase, a major player in active DNA demethylation. Chapter 3 will describe the identification and characterization of two additional stem cell coactivators: the DKC1 ribonucleoprotein and ABCF1. As it is with the case of the XPC DNA repair complex, DKC1 and ABCF1 are multifunctional proteins with unanticipated roles in pluripotent gene transcription.

In summary, this dissertation will highlight the role of versatile proteins in pluripotent stem cells and their involvement in transcriptional regulation and beyond. By strengthening our understanding of the fundamental molecular mechanisms employed by pluripotent stem cells, we may gain a better insight into how cell identity is specified.