Liu Zhiwen, Wan Xin, Chen Jiehui, Ma Yongjian, Fu Yonggao, Chen Yingying, Wen Mingzhu, Yang Yun, Qian Yun, Zhang Yong, Zhu Dahai, Li Jinsong, Jing Naihe, Yang Xianfa
Guangzhou National Laboratory, Guangzhou, Guangdong, China.
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
Cell Discov. 2025 Jun 3;11(1):53. doi: 10.1038/s41421-025-00805-0.
Inter-chromosomal interactions play a crucial role in 3D genome organization, yet the organizational principles and functional significances remain elusive. In general, lncRNA loci and transcripts are frequently associated with transcriptional programs modulated by long-range chromatin interactions. Here, we identified a novel lncRNA named Gm26793, which is abundantly distributed in the primitive streak and mesodermal cells of embryonic day 7.5 mouse gastrula. Through genetic ablation of Gm26793, we observed a preferential responsiveness to primitive endoderm lineage during stem cell differentiation, as well as enhanced occurrence of transient and degenerative state cells in early mouse embryos when the cell fate segregates between epiblast and primitive endoderm. Mechanistically, we revealed that the genomic locus of Gm26793, rather than the lncRNA transcript or adjacent gene, governs the cell fate preference towards primitive endoderm. Concretely, Gm26793 locus (Chromosome 7) forms an inter-chromosomal molecular lock with Cubn (Chromosome 2) via CTCF, restraining the expression of Cubn and maintaining a natural epigenetic landscape, thus ensuring the proper lineage specification in vitro and in vivo. Overall, our study provides a clear paradigm that inter-chromosomal interaction collaborates with architectural factors to stabilize nuclear conformation and guarantee faithful gene expression during stem cell differentiation and mammalian embryogenesis.
染色体间相互作用在三维基因组组织中起着关键作用，但其组织原则和功能意义仍不清楚。一般来说，长链非编码RNA（lncRNA）基因座和转录本经常与由远程染色质相互作用调节的转录程序相关联。在这里，我们鉴定了一种名为Gm26793的新型lncRNA，它大量分布在胚胎第7.5天小鼠原肠胚的原条和中胚层细胞中。通过对Gm26793进行基因敲除，我们观察到干细胞分化过程中对原始内胚层谱系的优先反应，以及当细胞命运在胚泡和原始内胚层之间分离时，早期小鼠胚胎中短暂和退化状态细胞的出现增加。从机制上讲，我们发现Gm26793的基因组位点，而不是lncRNA转录本或相邻基因，决定了细胞对原始内胚层的命运偏好。具体来说，Gm26793基因座（7号染色体）通过CTCF与Cubn（2号染色体）形成染色体间分子锁，抑制Cubn的表达并维持自然的表观遗传景观，从而确保体外和体内适当的谱系特化。总体而言，我们的研究提供了一个清晰的范例，即染色体间相互作用与结构因子协作，以稳定核构象并保证干细胞分化和哺乳动物胚胎发育过程中基因表达的忠实性。
