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

Area of Science:

• Epigenetics
• Molecular Biology
• Reproductive Biology

Background:

• The interplay between RNA methylation (m⁶A) and histone modifications in regulating endometrial receptivity is not well understood.
• Endometrial receptivity is crucial for successful implantation and pregnancy, and its dysregulation can lead to infertility.

Purpose of the Study:

• To elucidate the regulatory mechanism linking m⁶A RNA methylation and histone modification in endometrial receptivity.
• To investigate the role of Mettl3, Eed, and Ythdc1 in this process and their impact on chromatin accessibility and gene expression.

Main Methods:

• Utilized knockout models (Mettl3 deletion in the endometrium) to study the effects on m⁶A methylation and histone modifications.
• Investigated the interaction between Mettl3 and Eed and its influence on H3K27me3 suppression.
• Analyzed the recruitment of Ythdc1 and its role in recognizing m⁶A-modified RNA to regulate gene transcription.

Main Results:

• RIF induction led to decreased m⁶A and Mettl3 levels, impacting H3K27me3 modification and chromatin accessibility.
• Mettl3 deletion in the endometrium altered mRNA m⁶A methylation through Eed interaction, reducing Ythdc1-mediated suppression of H3K27me3.
• Reduced H3K27me3 resulted in disrupted chromatin accessibility and impaired transcription of key genes for endometrial receptivity.

Conclusions:

• Identified a novel Mettl3-Eed-m⁶A-Ythdc1 axis that connects m⁶A RNA methylation and histone modification.
• This axis regulates local chromatin state and gene expression, offering insights into the epigenetic crosstalk between RNA and DNA modifications.
• The findings advance the understanding of epigenetic mechanisms underlying infertility and may provide therapeutic targets.