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

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

  • Nucleic Acids Res. 2024 Aug 21:gkae707. doi: 10.1093/nar/gkae707.
Zechuan Liang 1 2,  Tao Huang 1 2,  Wei Li 3 4,  Zhaoyi Ma 1 2,  Kaipeng Wang 2 5,  Ziwei Zhai 3 4,  Yixin Fan 3 4,  Yu Fu 2 5,  Xiaomin Wang 2,  Yue Qin 2 6,  Bo Wang 2 7 8,  Chengchen Zhao 2 8 9,  Junqi Kuang 2 6 9,  Duanqing Pei 2 9
Affiliations

Affiliations

  • 1 College of Life Sciences, Zhejiang University, Hangzhou, China.
  • 2 Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou, China.
  • 3 CAS Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
  • 4 University of Chinese Academy of Sciences, Beijing, China.
  • 5 Fudan Unversity, Shanghai, China.
  • 6 Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, China.
  • 7 Zhejiang University of Science and Technology School of Information and Electronic Engineering, Hangzhou, China.
  • 8 Zhejiang Key Laboratory of Biomedical Intelligent Computing Technology, Hangzhou, China.
  • 9 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, Zhejiang, China.
PMID: 39166492 DOI: 10.1093/nar/gkae707
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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