Two Distinct E2F Transcriptional Modules Drive Cell Cycles and Differentiation
Maria C. Cuitiño, Thierry Pécot, Daokun Sun, Michael C. Ostrowski, Michele Pagano, Gustavo Leone
Open Access Published:May 23, 2019
Highlights
• E2F expression during cell division, differentiation, and quiescence is measured in vivo
• E2F expression during cell division, differentiation, and quiescence is measured in vivo
• E2F3A, E2F8, and E2F4 accumulate sequentially in the nucleus of cycling cells
• E2F3A-4 nuclear accumulation controls gene expression during cell-cycle exit
• Deep learning tools are applied to nuclear segmentation of complex mammalian tissues
Summary
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.
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