Genomic locus of lncRNA-Gm26793forms an inter-chromosomal molecular lock withCubnto ensure proper stem cell differentiation and mouse embryogenesis

Abstract

AbstractInter-chromosomal interactions play a crucial role in 3D genome organization, yet the organizational principles and functional significances remain elusive. In general, long non-coding RNA (lncRNA) loci and transcripts are frequently associated with transcriptional programs modulated by long-range chromatin interactions. Here, we identified a novel lncRNA namedGm26793, which is abundantly distributed in the primitive streak and mesodermal cells of E7.5 mouse gastrula. Through genetic ablation ofGm26793, 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 the genomic locus ofGm26793, rather than the lncRNA transcript or adjacent gene governs the cell fate preference towards primitive endoderm. Concretely,Gm26793locus (Chr 7) forms an inter-chromosomal molecular lock withCubn(Chr 2), restraining the expression ofCubnand maintaining a natural epigenetic landscape, thus ensuring the proper lineage specificationin vitroandin vivo. In order to reinforce this lock, CTCF and cohesin complex serves as a ring to fasten the inter-chromosomal contact. 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.