Role of Oct4 in Mammalian Embryonic Stem Cell Pluripotency


Pathway Description

Oct4 is a homeodomain transcription factor of the POU (Pit-Oct-Unc) family, which plays a central role in self-renewal, pluripotency, and lineage commitment in ESCs. Several positive and negative regulators bind to the Oct4 gene to regulate its expression. LRH-1, SF1 and RXR-β are positive regulators of Oct4. GCNF and COUF-TFI/II are potential negative regulators. Oct4 can also be degraded by interacting with a murine E3 Ub ligase,Wwp2.The most common regulators that cooperate with Oct4 in activating Oct4 target genes include Sox2 and NANOG. Oct4 and Sox2 reciprocally regulate POU5F1 and Sox2 transcription via the Oct4-Sox2 complex in ESCs. They also positively regulate NANOG. Besides, other ESC-specific enhancers that contain binding sites for Oct3/4 and Sox2 have been identified in several genes, including FGF4, SPP1, UTF1, FBXO15, and Lefty1 in human and Lig3, KCTD3, Bmi1 and NASP in mouse.

Thirty five genes implicated in chromatin remodeling are correlated to Oct4.Transcription factors such as ASH1L, ASH2L, Phc1, and RNF134, Bmi1, and Phc3 are also correlated to Oct4. While others are positive targets, Bmi1 and Phc3 are negative targets of Oct4. About 38 cell-cycle related genes are positively correlated to Oct4. Validated Oct4 target CCNF is implicated in cell cycle control at the G1/S and G2/M checkpoints and is associated with the maintenance of pRb in a hyperphosphorylated, inactive state. Conversely, the Oct4 correlated PP1 negative regulatory subunit NIPP1, facilitates the functional inactivation of pRb. Other cell cycle genes activated by Oct4 include D14Abb1E, IGF2BP1 and JARID1B, which inactivate Rb. Inactivation of pRb is required for self-renewal.

Twenty five apoptotic genes are found to be positively correlated to Oct4, the majority of which function to inhibit apoptosis. SH3GLB1 and caspase6 are negatively correlated to Oct4. Thirty genes implicated in DNA damage and repair, are also positively correlated to Oct4, of which TRP53, TDRD7, BRCA1, and PARP1 are direct Oct4 targets. TDRD7 plays an important role in DNA damage response, caspase3 in skeletal muscle differentiation and PARP1, TRP53 and BRCA1 help to modulate differentiation. TDRD7 is a negative target of Oct4.

Oct4 promotes self-renewal by inactivating genes which promote differentiation or by activating genes which inhibit differentiation. Most common genes positively regulated by Oct4 include RAR-α, REST, Aqr, JARID2 and SalL4. RAR-α, REST and Aqr inhibit ectoderm and mesoderm differentiation. Negative targets of Oct4 include MEF2A and HoxB1. In the initial stages of differentiation, HoxB1 is transcriptionally activated, which results in chromatin decondensation and reorientation of this locus to the nuclear center.

In human ESCs, Oct3/4 interacts with Cdx2, a trigger for trophectoderm differentiation, to form a repressor complex. Downregulation of Oct3/4 results in an upregulation of Cdx2, and vice versa. Oct4 represses gene expression either indirectly by neutralizing activators such as FoxD3, or directly by binding to promoters. Oct4 repress the expression of FoxA1 and FoxA2 through an interaction with the DNA binding domain of their activator FoxD3. Silencing of Ifn-Tau appears to be mediated by Oct4. Oct4 and Ets2 form a complex through interaction between the Oct4 POU domain and the DNA binding domain of Ets2 and as a result quench the transactivation function of Ets2. Oct4 is downregulated thus alleviating the co-repression of Ets2 to allow trophoectoderm specific genes such as Ifn-Tau to be expressed. Oct4 also binds to PSBP leading to NANOG gene expression. Oct4 dominantly binds to the octamer element, while PSBP preferentially binds to the Sox element. An understanding of Oct4 function in stem cell biology could lead to novel treatments for certain malignancies.


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