Live-cell imaging reveals the spatiotemporal organization of endogenous RNA polymerase II phosphorylation at a single gene

Nat Commun. 2021 May 26;12(1):3158. doi: 10.1038/s41467-021-23417-0.

Abstract

The carboxyl-terminal domain of RNA polymerase II (RNAP2) is phosphorylated during transcription in eukaryotic cells. While residue-specific phosphorylation has been mapped with exquisite spatial resolution along the 1D genome in a population of fixed cells using immunoprecipitation-based assays, the timing, kinetics, and spatial organization of phosphorylation along a single-copy gene have not yet been measured in living cells. Here, we achieve this by combining multi-color, single-molecule microscopy with fluorescent antibody-based probes that specifically bind to different phosphorylated forms of endogenous RNAP2 in living cells. Applying this methodology to a single-copy HIV-1 reporter gene provides live-cell evidence for heterogeneity in the distribution of RNAP2 along the length of the gene as well as Serine 5 phosphorylated RNAP2 clusters that remain separated in both space and time from nascent mRNA synthesis. Computational models determine that 5 to 40 RNAP2 cluster around the promoter during a typical transcriptional burst, with most phosphorylated at Serine 5 within 6 seconds of arrival and roughly half escaping the promoter in ~1.5 minutes. Taken together, our data provide live-cell support for the notion of efficient transcription clusters that transiently form around promoters and contain high concentrations of RNAP2 phosphorylated at Serine 5.

Publication types

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

MeSH terms

  • Genes, Reporter / genetics
  • Green Fluorescent Proteins / genetics
  • HeLa Cells
  • Humans
  • Intravital Microscopy / methods*
  • Microscopy, Fluorescence
  • Phosphorylation
  • Promoter Regions, Genetic
  • RNA Polymerase II / metabolism*
  • RNA, Messenger / biosynthesis
  • Serine / metabolism
  • Single Molecule Imaging / methods*
  • Spatio-Temporal Analysis
  • Time-Lapse Imaging
  • Transcription, Genetic*

Substances

  • RNA, Messenger
  • Green Fluorescent Proteins
  • Serine
  • RNA Polymerase II

Associated data

  • figshare/10.6084/m9.figshare.14187011