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

Two Distinct E2F Transcriptional Modules Drive Cell Cycles and Differentiation.

Author information

1
Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
2
Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Molecular Genetics, Ohio State University, Columbus, OH 43210, USA.
3
Department of Molecular Genetics, Ohio State University, Columbus, OH 43210, USA.
4
Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA.
5
Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
6
Department of Biochemistry and Molecular Pharmacology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
7
Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA; Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
8
Department of Biochemistry and Molecular Pharmacology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
9
Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: leoneg@musc.edu.

Abstract

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

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