YTHDC1 maintains trophoblasts function by promoting degradation of m6A-modified circMPP1

Area of Science:

• Epigenetics
• Molecular Biology
• Reproductive Biology

Background:

• N6-methyladenosine (m6A) is a prevalent mRNA modification in eukaryotes.
• Circular RNAs (circRNAs) play roles in gene regulation, but their function in placental development is not fully understood.
• Large-for-gestational-age (LGA) neonates are associated with placental dysfunction.

Purpose of the Study:

• To investigate the role of circMPP1 in placental villi function.
• To elucidate the molecular mechanism underlying circMPP1's effect on placental health.
• To identify potential therapeutic targets for placental impairment.

Main Methods:

• Screening of differentially expressed circRNAs in LGA neonates using m6A-circRNA Epitranscriptomic Microarray.
• Validation of circMPP1 expression by RT-qPCR.
• In vitro and in vivo functional experiments to assess circMPP1's impact.
• Identification of interacting proteins using RNA pull-down and RNA immunoprecipitation.
• Analysis of signaling pathways (NF-kappa B, MAPK3) and m6A modification (methylated RNA immunoprecipitation assay).

Main Results:

• CircMPP1 was found to be highly expressed in tissues with disordered placental function.
• CircMPP1 inhibited placental villi function and was associated with fetal dysplasia.
• CircMPP1 activated the NF-kappa B and MAPK3 signaling pathways.
• The m6A reader protein YTHDC1 was identified to reduce circMPP1 expression through m6A modification.

Conclusions:

• YTHDC1 maintains trophoblast function by promoting the degradation of m6A-modified circMPP1.
• CircMPP1 acts as a negative regulator of placental villi function.
• Targeting the YTHDC1-circMPP1 interaction may offer a therapeutic strategy for placental disorders.