KDM5A-driven H3K4me3 promotes aberrant neural development by Wnt/β-catenin pathway activation

Neural tube defects (NTDs) are common and severe birth defects. Folate supplementation can prevent NTDs, but the underlying molecular mechanisms are unclear. Aberrant Wnt/β-catenin pathway activation leads to defective anteroposterior patterning, resulting in NTDs, but little is known about whether epigenetic factors contribute to this process. Here, we performed ChIP and CUT&Tag to explore H3K4me3 in folate-deficient cells and NTDs mouse models. Our findings show folate deficiency increased H3K4me3 levels at Wnt target genes promoters, enhancing their transcription. This effect was mediated by reduced expression of histone demethylase KDM5A，leading to the maintenance of H3K4me3 marks and activation of Wnt/β-catenin signalling. Similarly, Wnt/β-catenin pathway was activated in KDM5A-KO cells and folate-deficient NTD mice. Intriguingly, KDM5A depletion in zebrafish embryos resulted in defective neurodevelopment and increased Wnt signalling. Furthermore, the transcription factor Pax2 downregulated KDM5A under folate-deficient conditions. Clinically, increased H3K4me3 levels and Wnt target genes expression were observed in low-folate NTDs brain samples. All these findings suggest KDM5A-dependent epigenetic regulation of Wnt signaling is crucial in low folate NTDs, implicating a potential therapeutic target.