title: Pausing of RNA polymerase II regulates mammalian developmental potential through control of signaling networks.
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.
authors.affiliation: Laboratory of Epigenetics and Stem Cell Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Lucy H
authors.initials: LH
authors.lastname: Williams
authors.affiliation: Laboratory of Epigenetics and Stem Cell Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: George
authors.initials: G
authors.lastname: Fromm
authors.affiliation: Laboratory of Epigenetics and Stem Cell Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Nolan G
authors.initials: NG
authors.lastname: Gokey
authors.affiliation: Laboratory of Epigenetics and Stem Cell Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Telmo
authors.initials: T
authors.lastname: Henriques
authors.affiliation: Laboratory of Epigenetics and Stem Cell Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Ginger W
authors.initials: GW
authors.lastname: Muse
authors.affiliation: Center for Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Burkholder
authors.affiliation: Center for Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Fargo
authors.affiliation: Laboratory of Epigenetics and Stem Cell Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Hu
authors.affiliation: Laboratory of Epigenetics and Stem Cell Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Adelman
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000201:enzymology*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D008322:Mammals / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012320:RNA Polymerase III / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C582413:NELF protein, mouse; D014157:Transcription Factors; D005346:Fibroblast Growth Factors; D012320:RNA Polymerase III