Regulation of Stem Cell Pluripotency and Differentiation Involves a Mutual Regulatory Circuit of the Nanog, OCT4, and SOX2 Pluripotency Transcription Factors With Polycomb Repressive Complexes and Stem Cell microRNAs

Abstract

Coordinated transcription factor networks have emerged as the master regulatory mechanisms of stem cell pluripotency and differentiation. Many stem cell-specifi c transcription factors, including the pluripotency transcription factors, OCT4, NANOG, and SOX2 function in combinatorial complexes to regulate the expression of loci, which are involved in embryonic stem (ES) cell pluripotency and cellular differentiation. This review will address how these pathways form a reciprocal regulatory circuit whereby the equilibrium between stem cell self-renewal, proliferation, and differentiation is in perpetual balance. We will discuss how distinct epigenetic repressive pathways involving polycomb complexes, DNA methylation, and microRNAs cooperate to reduce transcriptional noise and to prevent stochastic and aberrant induction of differentiation. We will provide a brief overview of how these networks cooperate to modulate differentiation along hematopoietic and neuronal lineages. Finally, we will describe how aberrant functioning of components of the stem cell regulatory network may contribute to malignant transformation of adult stem cells and the establishment of a "cancer stem cell" phenotype and thereby underlie multiple types of human malignancies.

Growth and Differentiation Factor 3 Is Transcriptionally Regulated by OCT4 in Human Embryonic Carcinoma Cells

“…Aberrant functioning of these stem cell regulators may influence malignant transformation and tumorigenesis. 5) Therefore, this study demonstrates that OCT4 plays a role as a transcriptional activator for GDF3 transcription in pluripotent NCCIT cells and contributes the understanding of the molecular networks of stem cell regulators in germ cellderived pluripotency and tumorigenesis.…”

“…3,4) OCT4 is a master regulator of the induction and maintenance of cellular pluripotency and its expression must be tightly regulated since dysregulation of OCT4 expression leads to a loss of pluripotency and induces differentiation in ES cells. [5][6][7] OCT4 is also expressed in histologically heterogeneous TGCTs. [8][9][10][11][12] In recent studies, OCT4 enhances the migration and invasion of bladder cancer cells and also promotes colony formation of glioma cells.…”

Geminin promotes neural fate acquisition of embryonic stem cells by maintaining chromatin in an accessible and hyperacetylated state

“…The pluripotent state of ES cells is maintained by a core transcriptional network involving Oct4, Sox2, and Nanog and characterized by a dynamic chromatin structure with loosely bound histones, which is permissive for the transcriptional machinery (8,9). Large-scale changes in chromatin structure accompany lineage commitment.…”

Multidrug Resistance Transporters – Roles in maintaining Cancer Stem-Like Cells

“…Together, miRNAs may represent important players in intrinsic or acquired MDR in cancer cells. With the general appreciation of the importance of miRNAs in gene regulation, an emerging role of miRNAs in regulating stem cell self-renewal and differentiation has been revealed (Kashyap et al, 2009), which are important for proper stem cell function and maintenance. Recently, the coordinated regulation of miRNAs and various stem cell transcription factors including OCT4, SOX2 and Nanog have emerged as the master regulatory mechanism for stem cells pluripotency and differentiation.…”