Transcriptional Burst Initiation and Polymerase Pause Release Are Key Control Points of Transcriptional Regulation

Mol Cell. 2019 Feb 7;73(3):519-532.e4. doi: 10.1016/j.molcel.2018.11.004. Epub 2018 Dec 13.


Transcriptional regulation occurs via changes to rates of different biochemical steps of transcription, but it remains unclear which rates are subject to change upon biological perturbation. Biochemical studies have suggested that stimuli predominantly affect the rates of RNA polymerase II (Pol II) recruitment and polymerase release from promoter-proximal pausing. Single-cell studies revealed that transcription occurs in discontinuous bursts, suggesting that features of such bursts like frequency and intensity could also be regulated. We combined Pol II chromatin immunoprecipitation sequencing (ChIP-seq) and single-cell transcriptional measurements to show that an independently regulated burst initiation step is required before polymerase recruitment can occur. Using a number of global and targeted transcriptional regulatory perturbations, we showed that biological perturbations regulated both burst initiation and polymerase pause release rates but seemed not to regulate polymerase recruitment rate. Our results suggest that transcriptional regulation primarily acts by changing the rates of burst initiation and polymerase pause release.

Keywords: single-molecule imaging; transcription; transcriptional bursting.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • Computer Simulation
  • GATA1 Transcription Factor / genetics
  • GATA1 Transcription Factor / metabolism
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Mice
  • Models, Genetic
  • Mouse Embryonic Stem Cells / enzymology*
  • Protein Binding
  • RNA / biosynthesis*
  • RNA / genetics
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism*
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Time Factors
  • Transcription Initiation Site*
  • Transcription Initiation, Genetic*
  • Transcriptional Activation*


  • GATA1 Transcription Factor
  • Membrane Transport Proteins
  • Receptors, Estrogen
  • mitoferrin protein, mouse
  • RNA
  • RNA Polymerase II