Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan Er Road, Yuexiu district, 510080 Guangzhou, China.
Nucleic Acids Res. 2024 Aug 12;52(14):8146-8164. doi: 10.1093/nar/gkae476.
During early development, gene expression is tightly regulated. However, how genome organization controls gene expression during the transition from naïve embryonic stem cells to epiblast stem cells is still poorly understood. Using single-molecule microscopy approaches to reach nanoscale resolution, we show that genome remodeling affects gene transcription during pluripotency transition. Specifically, after exit from the naïve pluripotency state, chromatin becomes less compacted, and the OCT4 transcription factor has lower mobility and is more bound to its cognate sites. In epiblast cells, the active transcription hallmark, H3K9ac, decreases within the Oct4 locus, correlating with reduced accessibility of OCT4 and, in turn, with reduced expression of Oct4 nascent RNAs. Despite the high variability in the distances between active pluripotency genes, distances between Nodal and Oct4 decrease during epiblast specification. In particular, highly expressed Oct4 alleles are closer to nuclear speckles during all stages of the pluripotency transition, while only a distinct group of highly expressed Nodal alleles are in close proximity to Oct4 when associated with a nuclear speckle in epiblast cells. Overall, our results provide new insights into the role of the spatiotemporal genome remodeling during mouse pluripotency transition and its correlation with the expression of key pluripotency genes.
在早期发育过程中，基因表达受到严格调控。然而，基因组组织如何在从原始胚胎干细胞到上胚层干细胞的过渡过程中控制基因表达仍知之甚少。我们使用单分子显微镜方法达到纳米级分辨率，表明基因组重排会影响多能性转变过程中的基因转录。具体来说，在退出原始多能性状态后，染色质变得不那么紧凑，OCT4 转录因子的流动性降低，并且与同源结合位点的结合更为紧密。在上胚层细胞中，活跃转录的标志 H3K9ac 在 Oct4 基因座内减少，与 OCT4 的可及性降低相关，进而与 Oct4 新生 RNA 的表达减少相关。尽管活跃的多能性基因之间的距离变化很大，但在胚胎发生指定过程中 Nodal 和 Oct4 之间的距离会减小。特别是在多能性转变的所有阶段，高表达的 Oct4 等位基因更接近核斑点，而只有一组特定的高表达 Nodal 等位基因在上胚层细胞与核斑点相关时才与 Oct4 接近。总体而言，我们的研究结果为小鼠多能性转变过程中时空基因组重排及其与关键多能性基因表达的相关性提供了新的见解。
