A lncRNA fine tunes the dynamics of a cell state transition involving Lin28, let-7 and de novo DNA methylation

Abstract

Execution of pluripotency requires progression from the naïve status represented by mouse embryonic stem cells (ESCs) to a state capacitated for lineage specification. This transition is coordinated at multiple levels. Non-coding RNAs may contribute to this regulatory orchestra. We identified a rodent-specific long non-coding RNA (lncRNA) <i>linc1281,</i> hereafter <i>Ephemeron</i> (<i>Eprn</i>), that modulates the dynamics of exit from naïve pluripotency. <i>Eprn</i> deletion delays the extinction of ESC identity, an effect associated with perduring Nanog expression. In the absence of <i>Eprn</i>, <i>Lin28a</i> expression is reduced which results in persistence of <i>let-7 microRNAs, and</i> the up-regulation of de novo methyltransferases Dnmt3a/b is delayed. <i>Dnmt3a/b</i> deletion retards ES cell transition, correlating with delayed <i>Nanog</i> promoter methylation and phenocopying loss of <i>Eprn</i> or <i>Lin28a</i>. 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. <i>Eprn</i> illustrates how lncRNAs may introduce species-specific network modulations.