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Mitotic bookmarking in the maintenance of embryonic stem cell identity

Gene expression determines cell identity and is controlled by various transcription factors. Understanding how cell identity is transmitted through division in stem cells is central for exploiting their therapeutic and regenerative potential.

Fundamental Research

Embryonic stem (ES) cells are able to differentiate into almost any cell type constituting the adult body, an ability defined as pluripotency. This renders them a promising tool for future therapeutic approaches aimed at replacing damaged cells and reconstitute functional tissues in patients. Pluripotency in ES cells depends on the activity of relatively well-characterised group of transcription factors (TFs), among which the core elements are Oct4 and Sox2. Additional accessory factors enable ES cells to rapidly proliferate while efficiently maintaining their pluripotent identity, including oestrogen related receptor beta (Esrrb). Ability of ES cells to indefinitely transmit pluripotency across cell division is remarkable, given their dependence on the activity of pluripotency TFs: like most TFs they should be displaced from compacted DNA during mitosis. DNA chemical modifications, however, are retained through cell division and are generally believed to guide the correct re-establishment of TF activity in daughter cells. Surprisingly, in ES cells such modifications are not essential. The EU-funded EFIMB project worked under the hypothesis that memory of active transcription in ES cells is maintained by the retention of one or several pluripotency TFs on mitotic chromatin. Researchers focused in particular on Esrrb. To study the binding of Esrrb in ES cells during division, they generated a cell line where Esrrb was fused to a fluorescent tag. Live cell microscopy showed that Esrrb globally retain binding to DNA during division and especially in proximity to genes of particular importance for ES cell identity. Similar to resting cells, mitotic localisation of Esrrb depended on its ability to dynamically bind to specific sequences of DNA. Depletion studies showed that Esrrb mitotic binding correlated with the fast reactivation of an important set of genes after division, providing a possible explanation for the stable transmission of cell identity after cell division. Collectively, the findings of the EFIMB project provide novel information on the mechanism of regulatory control over transcription and cell identity in ES cells and how it is inherited through mitosis. Long-term, this will inform protocols for the in-vitro expansion of undifferentiated progenitors or their directed differentiation into cell types of therapeutic relevance.

Keywords

ES cells, pluripotency, mitosis, EFIMB, Esrrb

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20 November 2019