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) $\textit{linc1281}$, hereafter $\textit{Ephemeron}$ ($\textit{Eprn}$), that modulates the dynamics of exit from naïve pluripotency. $\textit{Eprn}$ deletion delays the extinction of ESC identity, an effect associated with perduring Nanog expression. In the absence of $\textit{Eprn}$, Lin28a expression is reduced which results in persistence of let-7 microRNAs, and the up-regulation of de novo methyltransferases Dnmt3a/b is delayed. Dnmt3a/b deletion retards ES cell transition, correlating with delayed Nanog promoter methylation and phenocopying loss of $\textit{Eprn}$ or Lin28a. 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. $\textit{Eprn}$ illustrates how lncRNAs may introduce species-specific network modulations.