ALKBH5 governs human endoderm fate by regulating the DKK1/4-mediated Wnt/β-catenin activation.

ABSTRACT: N6-methyladenonsine (m6A) is ubiquitously distributed in mammalian mRNA. However, the precise involvement of m6A in early development has yet to be fully elucidated. Here, we report that deletion of the m6A demethylase ALKBH5 in human embryonic stem cells (hESCs) severely impairs definitive endoderm (DE) differentiation. ALKBH5-/- hESCs fail to undergo the primitive streak (PS) intermediate transition that precedes endoderm specification. Mechanistically, we show that ALKBH5 deficiency induces m6A hypermethylation around the 3' untranslated region (3'UTR) of GATA6 transcripts and destabilizes GATA6 mRNA in a YTHDF2-dependent manner. Moreover, GATA6 binds to the promoters of critical regulatory genes involved in Wnt/β-catenin signaling transduction, including the canonical Wnt antagonist DK

SUBMITTER: Liang Z 

PROVIDER: S-EPMC11472173 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature