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Fluctuating Ahr Levels Control the Choice between Pluripotency and Differentiation

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Review of “Repression of the Aryl Hydrocarbon Receptor Is Required to Maintain Mitotic Progression and Prevent Loss of Pluripotency of Embryonic Stem Cells” from Stem Cells by Stuart P. Atkinson

Studies from the laboratory of Alvaro Puga (University of Cincinnati, Ohio, USA) have demonstrated that continuing mouse embryonic stem cell (ESC) pluripotency requires the repression of the aryl hydrocarbon receptor (Ahr) transcription factor and environmental sensor [1]. Furthermore, the study also discovered that stimulating mESC differentiation correlated to the derepression of the Ahr promoter.

The group now returns with a new Stem Cells study in which they explore just how Ahr functions! Ko et al have discovered that Ahr expression in mESCs actually fluctuates, and those cells which lose Ahr repression display disrupted mitotic PP2A-CDC25B signaling leading to the loss of pluripotency and the onset of differentiation [2].

Initial analyses sought to assess whether Ahr acted like other differentiation-associated genes, in that some escape repression and continue to be expressed at a low level in a small number of cells [3]. Through these assessments, the authors found that Ahr expression in the mESC population fluctuates between states of expression and repression. Furthermore, cells that did express Ahr also expressed lower levels of pluripotency genes, such as Oct4 and Sox2, and of many signs of pluripotency-associated characteristics.

So how does Ahr derepression mediate this loss of pluripotency? Cell cycle analysis revealed that mESCs expressing Ahr exhibited prolonged mitosis due to the downregulation of Mid1 ubiquitin ligase expression, Pp2a phosphatase activity, and 14-3-3 regulatory protein expression. This all combines to increased Cdc25b phosphatase activity and decreased Cdk1 phosphorylation, thereby promoting mitotic entry but slowing down mitotic exit.

Finally, and perhaps most interestingly, the study tracked mESCs with different Ahr expression levels during embryoid body-mediated differentiation. These investigations found that while the bulk of the mESCs differentiated into cardiomyocytes, Ahr-expressing cells preferentially differentiated towards a neuroglia cell fate.

Another piece of the pluripotency network discovered, another link between pluripotency and the cell cycle revealed, and perhaps a new means to promote the lineage-specific differentiation of ESCs. Hopefully, further research will uncover whether this regulatory mechanism also occurs in human pluripotent cell types and whether specific regenerative therapies can take advantage of these new findings.

References

  1. Ko CI, Wang Q, Fan Y, et al. Pluripotency factors and Polycomb Group proteins repress aryl hydrocarbon receptor expression in murine embryonic stem cells. Stem Cell Res 2014;12:296-308.
  2. Ko C-I, Fan Y, de Gannes M, et al. Repression of the Aryl Hydrocarbon Receptor Is Required to Maintain Mitotic Progression and Prevent Loss of Pluripotency of Embryonic Stem Cells. STEM CELLS 2016;34:2825-2839.
  3. Carter MG, Sharov AA, VanBuren V, et al. Transcript copy number estimation using a mouse whole-genome oligonucleotide microarray. Genome Biol 2005;6:R61.