Two Distinct E2F Transcriptional Modules Drive Cell Cycles and Differentiation

Abstract

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. : The study of E2Fs in vivo has been challenging. Cuitiño et al. reconstruct the spatiotemporal expression of E2F activators (E2F3A) and canonical (E2F4) and atypical (E2F8) repressors during the mammalian cell cycle and propose that orchestrated accumulation of different E2F combinations control gene expression in proliferating (E2F3A-8-4) and differentiating (E2F3A-4) cells. Keywords: E2F, cell cycle, transcription, RNA-seq, E2F-tagged knockin mice, immunostaining, confocal microscopy, image analysis, deep learning, FUCCI mouse embryos