Transcriptional Regulatory Network in Embryonic Stem Cells


Pathway Description

Stem Cells are undifferentiated cells that can give rise to several lineages of differentiated cell types. Stem cells are characterized by their ability to self-renew and maintain pluripotency. Embryonic stem cells (ESCs) maintain their pluripotent state by expressing a battery of transcription factors including OCT4, SOX2 and NANOG. Other factors such as FOXD3 and FGF4 are also believed to play important role in pluripotency and self-renewal. OCT4, SOX2 and NANOG form a regulatory feedback circuit that maintains pluripotency in human and mouse ESCs. OCT4, SOX2 and NANOG bind to their own as well as each other's promoters, thus forming an interconnected auto-regulation loop to maintain the ESC identity. A negative feedback loop formed by NANOG, OCT4 and another pluripotent factor, FoxD3 have been reported. OCT4 maintains NANOG expression by directly binding to a NANOG promoter when present at a sub-steady level, but represses it when OCT4 is above the normal level. FoxD3 positively regulates NANOG to counter the repression effect of excess OCT4. Conversely, NANOG and FoxD3 function as activators for OCT4 expression. When the expression level of OCT4 rises above a steady level, it represses its own promoter.

OCT4, NANOG and SOX2 also contribute to the hallmark characteristics of ESCs by activation of target genes that activate pluripotency and self-renewal mechanisms and repression of signaling pathways that promote differentiation. The active targets include genes encoding components of chromatin remodeling and histone-modifying complexes (SMARCAD1, MYST3 and SET) which have general roles in transcriptional regulation and genes encoding transcription factors (REST, SKIL, HESX1 and STAT3). REST has been shown to function in part to repress neuronal specific genes such as L1CAM and CX36. The RIF1 gene regulates telomere length and is considered important for self-renewal. Another active gene induced by OCT4, NANOG and SOX2 simultaneously is ZIC3, which is important in embryonic ectoderm and mesoderm development.

Among transcriptionally repressed genes co-occupied by OCT4, SOX2 and NANOG are genes that specify transcription factors important for differentiation into extra-embryonic, endodermal, mesodermal and ectodermal lineages (HOXB1, HAND1, MEIS1, PAX6, LHX5, ONECUT1). Other transcriptionally repressed genes include ESXL1 and NEUROG1. ESXL1 is believed to have extra embryonic function whereas NEUROG1 is involved in neurogenesis by activating NEUROD1. Besides regulating genes simultaneously, OCT4, SOX2 and NANOG also regulate several genes independently. The balance between the levels of OCT4 and CDX2 influence the first overt lineage differentiation in the embryo. A similar balance between NANOG levels and the transcription factors GATA4 and GATA6 is necessary for differentiation into primitive endoderm.


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