Transcription Factors for the Modulation of Pluripotency and Reprogramming

ESCs, first isolated from mouse preimplantation blastocysts almost 30 years ago (Evans and Kaufman 1981;Martin 1981), are known for their ability to self-renew indefinitely in vitro.These cells are considered pluripotent because they can differentiate into cells of all three embryonic germ layers: the endoderm, mesoderm, and ectoderm.As ESCs differentiate, developmental potency becomes more restricted and they become either specialized adult progenitor cells or terminally differentiated cells.Although ESCs contain the same genetic material as other cell types in the body, they can be maintained in vitro in a perpetual self-renewing state that is poised for differentiation.Different cell types possess different transcriptomes, and it is the unique transcriptome within ESCs that allows them to assume this distinct pluripotent and self-renewing identity.This variation in transcriptome that comprises all of the expressed transcripts within the cell can be accounted for by a host of factors.Principally, DNA-binding proteins known as transcription factors that interact with regulatory regions of genes such as promoters and enhancers can modulate the expression of genetic elements.Therefore, unraveling the transcriptional regulatory network in ESCs will provide invaluable insights into the biological network that preserves ESC identity.In addition, given their broad differentiation capacities, ESCs are good models to study the mechanisms underlying cellular differentiation.Furthermore, mouse ESCs are amenable to genetic modifications, and these cells can be used for the generation of transgenic mouse models.Apart from murine ESCs, pluripotent stem cells have also been derived from human blastocysts (Thomson et al. 1998;Cowan et al. 2004).These human ESCs serve as an important cellular model to understand the pluripotency and self-renewing framework in the context of humans.In this regard, a comparative analysis of the transcriptional regulatory networks in both mouse and human ESCs will identify conserved and diverse regulatory mechanisms that govern ESC identity. PIVOTAL TRANSCRIPTION FACTORS IN ESCS: OCT4, SOX2, AND NANOGOct4 and Sox2 are two transcription factors that are critical for the maintenance of the ESC state.When the expression of Oct4 is reduced, ESCs undergo differentiation into trophoblast-like cells (Nichols et al. 1998;Niwa et al. 2000).Similarly, the ablation of Sox2 results in differentiation toward the trophectoderm lineage (Masui et al. 2007).The reduced expression of these transcription factors is detrimental to the preservation of ESC integrity, but their overexpression can also perturb the pluripotent and selfrenewing phenotypes of ESCs.A 50% increment in Oct4 expression can result in differentiation of ESCs into cells of the primitive endoderm (Niwa et al. 2000), whereas Sox2 overexpression causes ESCs to differentiate to neuronal cells (Kopp et al. 2008).On the other hand, certain transcription factors are able to sustain pluripotency when they are overexpressed in ESCs.For example, Nanog was