Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Nucleic Acids Res. 2012 Apr;40(8):3511-23. doi: 10.1093/nar/gkr1203. Epub 2011 Dec 17.
E2F transcription factors are known to be important for timely activation of G(1)/S and G(2)/M genes required for cell cycle progression, but transcriptional mechanisms for deactivation of cell cycle-regulated genes are unknown. Here, we show that E2F7 is highly expressed during mid to late S-phase, occupies promoters of G(1)/S-regulated genes and represses their transcription. ChIP-seq analysis revealed that E2F7 binds preferentially to genomic sites containing the TTCCCGCC motif, which closely resembles the E2F consensus site. We identified 89 target genes that carry E2F7 binding sites close to the transcriptional start site and that are directly repressed by short-term induction of E2F7. Most of these target genes are known to be activated by E2Fs and are involved in DNA replication, metabolism and DNA repair. Importantly, induction of E2F7 during G(0)-G(1)/S resulted in S-phase arrest and DNA damage, whereas expression of E2F7 during G(2)/M failed to disturb cell cycle progression. These findings provide strong evidence that E2F7 directly controls the downswing of oscillating G(1)/S genes during S-phase progression.
E2F 转录因子对于细胞周期进程中 G(1)/S 和 G(2)/M 基因的及时激活是重要的，但细胞周期调控基因失活的转录机制尚不清楚。在这里，我们表明 E2F7 在 S 期中期到晚期高度表达，占据 G(1)/S 调控基因的启动子并抑制其转录。ChIP-seq 分析表明，E2F7 优先结合含有 TTCCCGCC 基序的基因组位点，该基序与 E2F 共有基序非常相似。我们鉴定了 89 个靶基因，这些基因的启动子附近携带 E2F7 结合位点，并且它们的转录受到 E2F7 的短期诱导直接抑制。这些靶基因中的大多数已知被 E2Fs 激活，参与 DNA 复制、代谢和 DNA 修复。重要的是，在 G(0)-G(1)/S 期间诱导 E2F7 会导致 S 期停滞和 DNA 损伤，而在 G(2)/M 期间表达 E2F7 未能干扰细胞周期进程。这些发现为 E2F7 在 S 期进展过程中直接控制振荡 G(1)/S 基因的下降提供了有力证据。
