The LINC01612-DVL2-WNT axis promotes human endoderm differentiation

Long noncoding RNA in gene desert regions are 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 without protein coding ability during endoderm differentiation. Depletion of LINC01612, through either shRNA-mediated knockdown or promoter deletion, severely disrupts human endoderm differentiation. Mechanistically, LINC01612 interacts with DVL2, a WNT regulator essential for early development, and stabilizes DVL2 protein level by reducing its ubiquitination. Loss of LINC01612 or DVL2 impairs WNT signaling, while both WNT activation and DVL2 overexpression could restore endoderm differentiation capacity due to the absence of LINC01612. These findings reveal LINC01612 as a key regulator in human definitive endoderm differentiation through stabilizing DVL2 protein level and modulating WNT activity.