Pausing of RNA polymerase II regulates mammalian developmental potential through control of signaling networks

Mol Cell. 2015 Apr 16;58(2):311-322. doi: 10.1016/j.molcel.2015.02.003. Epub 2015 Mar 12.

Abstract

The remarkable capacity for pluripotency and self-renewal in embryonic stem cells (ESCs) requires a finely tuned transcriptional circuitry wherein the pathways and genes that initiate differentiation are suppressed, but poised to respond rapidly to developmental signals. To elucidate transcriptional control in mouse ESCs in the naive, ground state, we defined the distribution of engaged RNA polymerase II (Pol II) at high resolution. We find that promoter-proximal pausing of Pol II is most enriched at genes regulating cell cycle and signal transduction and not, as expected, at developmental or bivalent genes. Accordingly, ablation of the primary pause-inducing factor NELF does not increase expression of lineage markers, but instead causes proliferation defects, embryonic lethality, and dysregulation of ESC signaling pathways. Indeed, ESCs lacking NELF have dramatically attenuated FGF/ERK activity, rendering them resistant to differentiation. This work thus uncovers a key role for NELF-mediated pausing in establishing the responsiveness of stem cells to developmental cues.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Embryonic Stem Cells / enzymology*
  • Fibroblast Growth Factors / metabolism
  • Gene Expression Regulation
  • Mammals / growth & development*
  • Mammals / metabolism
  • Mice
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • RNA Polymerase III / metabolism*
  • Signal Transduction*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • NELF protein, mouse
  • Transcription Factors
  • Fibroblast Growth Factors
  • RNA Polymerase III

Associated data

  • GEO/GSE43390