Transcriptional Pause Sites Delineate Stable Nucleosome-Associated Premature Polyadenylation Suppressed by U1 snRNP

Mol Cell. 2018 Feb 15;69(4):648-663.e7. doi: 10.1016/j.molcel.2018.01.006. Epub 2018 Feb 1.


Regulation of RNA polymerase II (Pol II) elongation is a critical step in gene regulation. Here, we report that U1 snRNP recognition and transcription pausing at stable nucleosomes are linked through premature polyadenylation signal (PAS) termination. By generating RNA exosome conditional deletion mouse embryonic stem cells, we identified a large class of polyadenylated short transcripts in the sense direction destabilized by the RNA exosome. These PAS termination events are enriched at the first few stable nucleosomes flanking CpG islands and suppressed by U1 snRNP. Thus, promoter-proximal Pol II pausing consists of two processes: TSS-proximal and +1 stable nucleosome pausing, with PAS termination coinciding with the latter. While pausing factors NELF/DSIF only function in the former step, flavopiridol-sensitive mechanism(s) and Myc modulate both steps. We propose that premature PAS termination near the nucleosome-associated pause site represents a common transcriptional elongation checkpoint regulated by U1 snRNP recognition, nucleosome stability, and Myc activity.

Keywords: Pol II pausing; U1-PAS axis; divergent transcription; exosome; nucleosome; premature termination.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Exosome Multienzyme Ribonuclease Complex / genetics
  • Exosome Multienzyme Ribonuclease Complex / metabolism
  • Gene Expression Regulation*
  • HEK293 Cells
  • Humans
  • Mice
  • Nucleosomes / physiology*
  • Polyadenylation*
  • Promoter Regions, Genetic
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism*
  • Ribonucleoprotein, U1 Small Nuclear / genetics
  • Ribonucleoprotein, U1 Small Nuclear / metabolism*
  • Spliceosomes / genetics
  • Spliceosomes / metabolism*
  • Transcription Elongation, Genetic*
  • Transcription Factors


  • Nucleosomes
  • Ribonucleoprotein, U1 Small Nuclear
  • Transcription Factors
  • RNA Polymerase II
  • Exosome Multienzyme Ribonuclease Complex