Mettl3/Eed/Ythdc1 regulatory axis controls endometrial receptivity and function

The regulatory mechanism between N6-methyladenosine (m⁶A) RNA methylation and histone modification in endometrial receptivity remains poorly understood. In this study, we depict that RIF induced m⁶A and Mettl3 level restrain, affecting H3K27me3 modification and chromatin accessibility. We show that Mettl3 deletion in the endometrium alters mRNA m⁶A methylation via Eed interaction. This reduces m⁶A recognized by Ythdc1, which recruits Eed to suppress H3K27me3 modification co-transcriptionally. The reduction of H3K27me3 disrupts chromatin accessibility and impairs transcription of genes critical for endometrial receptivity. Collectively, these results shed light on a Mettl3-Eed-m⁶A-Ythdc1 axis that links m⁶A and histone modification in regulating local chromatin state and gene expression, advancing our understanding of the epigenetic crosstalk between RNA and DNA modification in infertility disease.