Functional Interaction of <scp>GCM1</scp> and <scp>LINC01118</scp> Regulates Syncytiotrophoblast Differentiation

Human trophoblast stem (TS) cells differentiate into syncytiotrophoblasts (STBs) through cell-cell fusion, forming the outermost layer of the placental villus to enable nutrient and gas exchange between the mother and fetus. GCM1 (glial cells missing 1) is a placenta-specific transcription factor that regulates STB differentiation by activating the transcription of syncytin and hCGβ genes. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that do not encode proteins. While recent studies suggest that lncRNAs regulate cell differentiation, their role in STB differentiation remains unclear. In this study, we analyzed the transcriptomics of TS cells, as well as TS cell-derived STBs and extravillous trophoblasts, and identified a correlation between the expression of LINC01118 lncRNA and STB-related genes. LINC01118 is highly expressed in first-trimester STBs in the human placenta and is upregulated in BeWo and TS cells upon induction of STB differentiation. Notably, LINC01118 directly interacts with GCM1, enhancing its protein stability and thereby its transcriptional activity, which supports GCM1 autoregulation and the expression of downstream target genes involved in trophoblast fusion and hormone production. In conclusion, we identify LINC01118 as a novel lncRNA that positively regulates GCM1 activity, playing a key role in STB differentiation through its direct interaction with GCM1.