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

Elife. 2017 Aug 18;6:e23468. doi: 10.7554/eLife.23468.

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) linc1281, hereafter Ephemeron (Eprn), that modulates the dynamics of exit from naïve pluripotency. Eprn deletion delays the extinction of ESC identity, an effect associated with perduring Nanog expression. 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. Dnmt3a/b deletion retards ES cell transition, correlating with delayed Nanog promoter methylation and phenocopying loss of 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. Eprn illustrates how lncRNAs may introduce species-specific network modulations.

Keywords: Lin28a/Mirlet7; de novo DNA methylation; developmental biology; long non-coding RNA; mouse; pluripotency; stem cell transition; stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation*
  • Gene Deletion
  • Gene Expression Regulation*
  • Mice
  • MicroRNAs / metabolism*
  • Mouse Embryonic Stem Cells / physiology*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA-Binding Proteins / metabolism*

Substances

  • Lin-28 protein, mouse
  • MicroRNAs
  • RNA, Long Noncoding
  • RNA-Binding Proteins
  • mirnlet7 microRNA, mouse
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • DNA methyltransferase 3B