ArticleNucleic acids research2024
ALKBH5 governs human endoderm fate by regulating the DKK1/4-mediated Wnt/β-catenin activation.
Article in Nucleic acids research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
7 citing papers in PubMed.
- The Role of NMedComm · 2026Review
- Emerging Dual Roles of ALKBH5 in Ischemia-reperfusion Injury: Mechanisms and Therapeutic Implications.Cell biochemistry and biophysics · 2026Review
- Decoding m6A: a new frontier in maternal-foetal immunology.Frontiers in immunology · 2026Review
- Context-dependent functions of ALKBH5: a mechanistic framework linking cellular stress responses, immune regulation, viral infection, and therapeutic vulnerabilities.Frontiers in immunology · 2026Review
- Targeting of the mNature communications · 2025Article
- M6A Demethylase ALKBH5 in Human Diseases: From Structure to Mechanisms.Biomolecules · 2025Review
- ALKBH5 in development: decoding the multifaceted roles of mFrontiers in molecular biosciences · 2025Review
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Authors and funding
14 authors.
Funding
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 DKK1 and DKK4, which are unexpectedly repressed upon the dysregulation of GATA6 mRNA metabolism. Remarkably, DKK1 and DKK4 both exhibit a pleiotropic effect in modulating the Wnt/β-catenin cascade and guard the endogenous signaling activation underlying DE formation as potential downstream targets of the ALKBH5-GATA6 regulation. Here, we unravel a role of ALKBH5 in human endoderm formation in vitro by modulating the canonical Wnt signaling logic through the previously unrecognized functions of DKK1/4, thus capturing a more comprehensive role of m6A in early human embryogenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.