The elevated YTHDC1 affects trophoblastic function and induces preterm birth in ART conception via augmenting RPL37 translation

Here, it is shown that YTHDC1 was significantly increased in the human preterm placenta after ART and the murine preterm placenta after E2 exposure. Overexpression of YTHDC1 significantly promoted the proliferation, migration, and invasion of trophoblast cells, but inhibited their apoptosis. Knockdown or knockout of YTHDC1 played an opposite effect. Mechanistically, E2 promoted YTHDC1 expression through retinoid X receptor alpha (RXRA) upregulation. YTHDC1 could activate WNT and JAK/STAT signaling pathways in the human trophoblast cells. Meanwhile, YTHDC1 could fine-tone the translation of ribosomal protein L37 (RPL37) in a m6A-dependent manner, which then influence the cellular total protein synthesis. Importantly, administration of siRNA targeting YTHDC1 effectively delays preterm birth in vivo. Collectively, these findings uncover the epigenetic mechanism underlying ART preterm birth and provide a potential target for therapeutic intervention. To investigate the biological functions of YTHDC1 in human trophoblast cells, we applied siRNA against YTHDC1 to transiently knockdown YTHDC1 in HTR-8/SVneo cells. RNA immunoprecipitation followed by sequencing (RIP-seq) was performed using antibody against YTHDC1 to identify the targeted transcripts enriched by YTHDC1 in HTR-8/SVneo cells. m6A-RNA immunoprecipitation followed by sequencing (MeRIP-seq) was performed to identify the m6A sites across mRNA in HTR-8/SVneo cells. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) was performed using indicated antibodies to study the H3K27ac status and binding sites of transcription factor RXRA in HTR-8/SVneo cell.