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In contrast, ESCs can be suspended in a ground state of pluripotency, where self-renewal is decoupled from lineage specification, using two inhibitors (2i) of glycogen synthase kinase 3 (GSK3) and mitogen-activated protein kinase kinase (MEK1/2), along with the cytokine leukaemia inhibitory factor (LIF) ( Ying et al., 2008). In the embryo, spatially and temporally coordinated signals direct the rapid and continuous transition of the epiblast towards lineage specification ( Acampora et al., 2016 Smith, 2017). These properties make them an attractive system for investigating cell fate decision making. Mouse embryonic stem cells (ESCs), in vitro counterparts of the pre-implantation epiblast, exhibit dual properties of self-renewal and differentiation ( Boroviak et al., 2015 Bradley et al., 1984 Evans and Kaufman, 1981 Martin, 1981). Eprn illustrates how lncRNAs may introduce species-specific network modulations. The connection from lncRNA to miRNA and DNA methylation facilitates the acute extinction of naïve pluripotency, a pre-requisite for rapid progression from preimplantation epiblast to gastrulation in rodents. Dnmt3a/b deletion retards ES cell transition, correlating with delayed Nanog promoter methylation and phenocopying loss of Eprn or Lin28a. In the absence of Eprn, Lin28a expression is reduced which results in persistence of let-7 microRNAs, and the up-regulation of de novo methyltransferases Dnmt3a/b is delayed.

Eprn deletion delays the extinction of ESC identity, an effect associated with perduring Nanog expression. We identified a rodent-specific long non-coding RNA (lncRNA) linc1281, hereafter Ephemeron ( Eprn), that modulates the dynamics of exit from naïve pluripotency. Non-coding RNAs may contribute to this regulatory orchestra. This transition is coordinated at multiple levels. Execution of pluripotency requires progression from the naïve status represented by mouse embryonic stem cells (ESCs) to a state capacitated for lineage specification.