Abstract：
Precise regulation of the cell cycle of embryonic stem cells (ESCs) is critical for their self-maintenance and differentiation. The cell cycle of ESCs differs from that of somatic cells and is different depending on the cell culture conditions. However, the cell cycle regulation in ESCs via epigenetic mechanisms remains unclear. Here, we showed that the ATP-dependent chromatin remodeler Ino80 regulates the cell cycle genes in ESCs under primed conditions. Ino80 loss led to a significantly extended length of the G1-phase in ESCs grown under primed culture conditions. Ino80 directly bound to the transcription start site and regulated the expression of cell cycle-related genes. Furthermore, Ino80 loss induced cell apoptosis. However, the regulatory mechanism of Ino80 in differentiating ESC cycle slightly differed; an extended S-phase was detected in differentiating inducible Ino80 knockout ESCs. RNA-seq analysis of differentiating ESCs revealed that the expression of genes associated with organ development cell cycle is persistently altered in Ino80 knockout cells, suggesting that cell cycle regulation by Ino80 is not limited to undifferentiated ESCs. Therefore, our study establishes the function of Ino80 in ESC cycle via transcriptional regulation, at least partly. Moreover, this Ino80 function may be universal to other cell types.
摘要：
胚胎干细胞（ESC）细胞周期的精确调节对于其自我维持和分化至关重要。ESC的细胞周期不同于体细胞的细胞周期,并且根据细胞培养条件而不同。然而,通过表观遗传机制调节ESCs的细胞周期仍不清楚.这里,我们表明，ATP依赖性染色质重塑因子Ino80在引发条件下调节ESC的细胞周期基因。Ino80损失导致在引发的培养条件下生长的ESC中G1期的长度显著延长。Ino80直接与转录起始位点结合并调节细胞周期相关基因的表达。此外，Ino80丢失诱导细胞凋亡。然而,Ino80在分化ESC周期中的调节机制略有不同；在分化诱导型Ino80敲除ESC中检测到延长的S期。分化ESC的RNA-seq分析显示，与器官发育细胞周期相关的基因表达在Ino80敲除细胞中持续改变，这表明Ino80对细胞周期的调控不仅限于未分化的ESC。因此,我们的研究通过转录调控建立了Ino80在ESC周期中的功能，至少部分。此外，这种Ino80功能可能对其他细胞类型是通用的。
