# The LINC01612-DVL2-WNT axis promotes human endoderm differentiation

## TL;DR

The study identifies a long noncoding RNA, LINC01612, that supports human endoderm differentiation by stabilizing a key WNT signaling protein called DVL2.

## Contribution

LINC01612 is newly characterized as a desert lncRNA that promotes endoderm differentiation via the DVL2-WNT signaling axis.

## Key findings

- LINC01612 depletion impairs human definitive endoderm differentiation.
- LINC01612 stabilizes DVL2 protein by reducing its ubiquitination.
- WNT signaling is impaired in the absence of LINC01612 or DVL2.

## Abstract

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.

•LINC01612 is a highly expressed desert lncRNA during endoderm differentiation•LINC01612 promotes human endoderm differentiation through WNT signaling•DVL2 is the key functional target of LINC01612•LINC01612 interacts with and stabilizes DVL2 protein to sustain WNT signaling activity

LINC01612 is a highly expressed desert lncRNA during endoderm differentiation

LINC01612 promotes human endoderm differentiation through WNT signaling

DVL2 is the key functional target of LINC01612

LINC01612 interacts with and stabilizes DVL2 protein to sustain WNT signaling activity

Li and colleagues identify LINC01612 as a new endoderm-specific desert lncRNA required for human endoderm differentiation. Mechanistically, LINC01612 interacts with and stabilizes DVL2 by reducing its ubiquitination, thereby promoting WNT signaling.