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

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.AS is supported by Medical Research Council (G1100526/1), Biotechnology and Biological Sciences Research Council (BB/M004023/1), European Commission (HEALTH-F4-2007-200720 EUROSYSTEM), and Wellcome Trust (091484/Z/ 10/Z). LH is supported by National Cancer Institute (R01 CA139067, 1R21CA175560-01) and California Institute of Regenerative Medicine (RN2-00923-1), American Cancer Society (123339-RSG-12- 265-01-RMC), Tobacco-related Disease Research Program (21RT-0133). DLS is supported by NIGMS 42694 and NCI 5PO1CA013106-Project 3. TK is supported by programme grants from Cancer Research UK (C6/A18796) and European Research Council CRIPTON Grant (268569) and core grants from the Wellcome Trust (092096) and Cancer Research UK (C6946/A14492). The Cambridge Stem Cell Institute receives core funding from the Wellcome Trust and the Medical Research Council. MAL was a Siebel postdoctoral fellow at the University of California, Berkeley and a Sir Henry Wellcome postdoctoral fellow (096125/Z/11/Z). AS is a Medical Research Council Professor