Two Distinct E2F Transcriptional Modules Drive Cell Cycles and Differentiation

Cell Rep. 2019 Jun 18;27(12):3547-3560.e5. doi: 10.1016/j.celrep.2019.05.004. Epub 2019 May 23.


Orchestrating cell-cycle-dependent mRNA oscillations is critical to cell proliferation in multicellular organisms. Even though our understanding of cell-cycle-regulated transcription has improved significantly over the last three decades, the mechanisms remain untested in vivo. Unbiased transcriptomic profiling of G0, G1-S, and S-G2-M sorted cells from FUCCI mouse embryos suggested a central role for E2Fs in the control of cell-cycle-dependent gene expression. The analysis of gene expression and E2F-tagged knockin mice with tissue imaging and deep-learning tools suggested that post-transcriptional mechanisms universally coordinate the nuclear accumulation of E2F activators (E2F3A) and canonical (E2F4) and atypical (E2F8) repressors during the cell cycle in vivo. In summary, we mapped the spatiotemporal expression of sentinel E2F activators and canonical and atypical repressors at the single-cell level in vivo and propose that two distinct E2F modules relay the control of gene expression in cells actively cycling (E2F3A-8-4) and exiting the cycle (E2F3A-4) during mammalian development.

Keywords: E2F; E2F-tagged knockin mice; FUCCI mouse embryos; RNA-seq; cell cycle; confocal microscopy; deep learning; image analysis; immunostaining; transcription.

Publication types

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

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Cycle*
  • Cell Differentiation*
  • Cell Proliferation
  • Cells, Cultured
  • E2F3 Transcription Factor / physiology*
  • E2F4 Transcription Factor / physiology*
  • Female
  • Gene Expression Regulation*
  • Male
  • Mice
  • Mice, Knockout
  • Promoter Regions, Genetic
  • Repressor Proteins / physiology*
  • Transcriptome


  • Cell Cycle Proteins
  • E2F3 Transcription Factor
  • E2F4 Transcription Factor
  • E2F8 protein, mouse
  • E2f3 protein, mouse
  • E2f4 protein, mouse
  • Repressor Proteins