IMP1-interactive lncRNA regulates human endoderm differentiation via stabilizing WNT targets

ABSTRACT: Long noncoding RNAs (lncRNAs) have been shown to play important roles in diverse biological process, including embryonic development and cell differentiation. Extensive studies have revealed the function and mechanism of those lncRNAs adjacent to protein-coding genes (PCGs), but there are relatively fewer reports about the lncRNAs within gene desert, particularly in human early germ layer differentiation. Here based on transcriptome analysis during human definitive endoderm (DE) differentiation, we identified a “desert” lncRNA named CTD-2501M5.1, a cytoplasm-located transcript with no protein-coding gene nearby within the 50 kb genomic region, highly expressed in human definitive endoderm. Depletion of CTD-2501M5.1 by either shRNA or promoter deletion could cause the deficiency of DE differentiation from human pluripotent stem cells (PSCs). The biochemical analysis showed that CTD-2501M5.1 functionally interacted with insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1, also named IMP1), which is necessary for endoderm differentiation demonstrated by loss-of-function assay. We further found depletion of CTD-2501M5.1 could result in reduced WNT signaling activities. More importantly, manipulating WNT activity by chemicals could rescue the phenotype of DE deficiency due to the depletion of CTD-2501M5.1 or IMP1. Mechanistically, CTD-2501M5.1 facilitated the interaction between IMP1 and FZD5 mRNA, stabilizing FZD5 which is required for WNT signaling activation and DE differentiation. Ultimately, our study not only revealed the biological function of a novel desert lncRNA CTD-2501M5.1 in human DE differentiation, but also underlined lncRNA-mediated mRNA stability regulation via IMP1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188501 | GEO | 2023/03/30

REPOSITORIES: GEO