Repression of the Aryl Hydrocarbon Receptor Is Required to Maintain Mitotic Progression and Prevent Loss of Pluripotency of Embryonic Stem Cells

Abstract

Lack of cell cycle checkpoints and uninterrupted passage through S-phase continuously renew the embryonic stem (ES) cell population and maintain pluripotency. Here, we show that to regulate mitotic progression and pluripotency ES cells must keep the aryl hydrocarbon receptor (AHR), an environmental sensor and transcriptional regulator, in a persistent state of repression. This repression, however, is not always absolute, causing the AHR to fluctuate between reversible states of expression and repression, with a fraction of the cells escaping repression at any one time. Cells that escape AHR repression exhibit reduced levels of the pluripotency factors OCT4 and SOX2 and show an extended mitotic traverse time due to AHR-dependent MID1 repression and the subsequent disruption of the MID1-PP2A-CDC25B-CDK1 signaling pathway that regulates mitosis. Unlike the bulk of the cell population that differentiates into cardiomyocytes upon stimulation, AHR-expressing ES cells restrict cardiogenesis and commit to a neuroglia cell fate. It appears that the untimely expression of the Ahr gene needs to be repressed to maintain ES cell mitotic progression and prevent premature loss of pluripotency. Stem Cells 2016;34:2825-2839.

Does the aryl hydrocarbon receptor regulate pluripotency?

“…These observations suggest that the AHR may play a stage-dependent developmental function, possibly behaving as a differentiation-promoting factor that opposses pluripotency. Consistent with this hypothesis, our recent study suggests that Ahr expression must be repressed lest the ES cells would slow down proliferation and lose pluripotency [18, 21]. A similar AHR expression pattern and regulatory function is found in the differentiation of hematopoietic stem cells and cancer stem cells [36-39] suggestive of a widespread AHR function in the ontogeny of diverse stem cell lineages.…”

“…In these cells, AHR could regulate pluripotency by controlling both self-renewal and gene expression at the transcriptional level, balancing the expression of the pluripotency factors OCT4, NANOG and SOX2 and of differentiation related markers [18]. Under physiological conditions, Ahr is repressed in the ES cells, but its untimely derepression causes pluripotency loss and mitotic delay.…”

“…Several lines of evidence support the view that the AHR safeguards normal embryogenesis by coordinating the choices between proliferation and differentiation, two concerted processes that eventually bring about pluripotency loss [18-20]. Appropriate control of AHR expression appears to be essential to maintain pluripotency, an objective that the blastomeres attain by maintaining the AHR in a state of positive repression mediated by the pluripotency factors themselves in combination with Polycomb Group repressors [18, 21]. AHR repression may provide the ICM cells with the opportunity to reprogram gene expression, implementing epigenetic mechanisms that bring about global changes in DNA methylation [22-27].…”

Aryl hydrocarbon receptor (AHR): “pioneer member” of the basic-helix/loop/helix per - Arnt - sim (bHLH/PAS) family of “sensors” of foreign and endogenous signals

“…Any undesirable early expression of AHR in specific cells of the developing early embryo must therefore be repressed, in order to maintain ES cell mitotic progression and to prevent premature loss of pluripotency (Ko et al , 2016). …”

“…disruption of the MID1-PP2A-CDC25B/26-CDK1 signaling pathway (Fig. 8A) that regulates mitosis (Ko et al , 2016). …”