The LINC01612-DVL2-WNT axis promotes human endoderm differentiation

Long noncoding RNAs in gene desert regions remain largely uncharacterized despite their potential regulatory roles in cell differentiation. Here, we identify LINC01612 as a crucial modulator of human definitive endoderm differentiation. LINC01612 exhibits stage-specific expression and lacks protein-coding potential during endoderm differentiation. Depletion of LINC01612, through either short hairpin RNA (shRNA)-mediated knockdown or promoter deletion, severely impairs human endoderm differentiation. Mechanistically, LINC01612 interacts with DVL2, a WNT regulator essential for early development, and enhances DVL2 protein stability by reducing its ubiquitination. Loss of LINC01612 or DVL2 impairs WNT signaling, while both WNT activation and DVL2 overexpression can rescue endoderm differentiation defect in the absence of LINC01612. These findings reveal the LINC01612-DVL2-WNT regulatory axis as a key modulator of human definitive endoderm differentiation.