IDR/Westmead Institute for Medical Research, NSW 2145, Australia.
School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, NSW 2006, Australia.
Nucleic Acids Res. 2021 Oct 11;49(18):10419-10430. doi: 10.1093/nar/gkab800.
A core imprint of metazoan life is that perturbations of cell cycle are offset by compensatory changes in successive cellular generations. This trait enhances robustness of multicellular growth and requires transmission of signaling cues within a cell lineage. Notably, the identity and mode of activity of transgenerational signals remain largely unknown. Here we report the discovery of a natural antisense transcript encoded in exon 25 of notch-1 locus (nAS25) by which mother cells control the fate of notch-1 transcript in daughter cells to buffer against perturbations of cell cycle. The antisense transcript is transcribed at G1 phase of cell cycle from a bi-directional E2F1-dependent promoter in the mother cell where the titer of nAS25 is calibrated to the length of G1. Transmission of the antisense transcript from mother to daughter cells stabilizes notch-1 sense transcript in G0 phase of daughter cells by masking it from RNA editing and resultant nonsense-mediated degradation. In consequence, nAS25-mediated amplification of notch-1 signaling reprograms G1 phase in daughter cells to compensate for the altered dynamics of the mother cell. The function of nAS25/notch-1 in integrating G1 phase history of the mother cell into that of daughter cells is compatible with the predicted activity of a molecular oscillator, slower than cyclins, that coordinates cell cycle within cell lineage.
后生动物生命的一个核心印记是，细胞周期的扰动会被后续细胞世代的代偿性变化所抵消。这种特性增强了多细胞生长的稳健性，并需要在细胞谱系内传递信号线索。值得注意的是，跨代信号的身份和活动模式在很大程度上仍然未知。在这里，我们报告了通过母体细胞中双向 E2F1 依赖性启动子在细胞周期的 G1 期转录编码 Notch-1 基因座（nAS25）外显子 25 的天然反义转录本（nAS25）的发现，该转录本控制 notch-1 转录本在子细胞中的命运，以缓冲细胞周期的扰动。反义转录本在母体细胞的 G1 期从双向 E2F1 依赖性启动子转录，其中 nAS25 的滴度与 G1 的长度相匹配。反义转录本从母体细胞向子细胞传递，通过掩盖其免受 RNA 编辑和由此产生的无意义介导的降解，稳定子细胞中 notch-1 有意义转录本在 G0 期。结果，nAS25 介导的 notch-1 信号放大将子细胞的 G1 期重新编程，以补偿母体细胞动态的变化。nAS25/notch-1 将母体细胞的 G1 期历史整合到子细胞中的功能与分子振荡器的预测活性兼容，分子振荡器的速度比细胞周期蛋白慢，它协调细胞谱系内的细胞周期。
