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.
Coordinated transcription factor networks have emerged as the master regulatory mechanisms of stem cell pluripotency and differentiation. Many stem cell-specific 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.
Kashyap
Vasundhra
V
Department of Pharmacology, Graduate Programs in Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA.
Rezende
Naira C
NC
Scotland
Kymora B
KB
Shaffer
Sebastian M
SM
Persson
Jenny Liao
JL
Gudas
Lorraine J
LJ
Mongan
Nigel P
NP
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000502:physiology; D044127:Epigenesis, Genetic / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
D018398:Homeodomain Proteins; D035683:MicroRNAs; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors