Work

Upregulated YTHDC1 mediates trophoblastic dysfunction inducing preterm birth in ART conceptions through enhanced RPL37 translation

Year: 2024

Type: article

Abstract: Assisted reproductive technology (ART) pregnancies present a higher risk of singleton preterm birth than natural pregnancies, but the underlying molecular mechanism remains largely unknown. RNA m 6 A modification is a key epigenetic mechanism regulating cellular function, but the role of m 6 A modification, especially its “reader” YTHDC1, in preterm delivery remains undefined. To delineate the role and epigenetic mechanism of m 6 A modification in ART preterm delivery, the effects of YTHDC1 on trophoblastic function were evaluated by CCK-8, EdU, Transwell, and flow cytometry analyses post its overexpression or knockdown. Downstream signaling pathways of YTHDC1 were investigated by RNA-seq, and targeted mRNAs were explored by RIP-seq and MeRIP-seq. Upstream transcriptional factors of YTHDC1 were determined by ChIP-seq and luciferase reporter assays. Elevated YTHDC1 was detected in human ART-conceived preterm placentas and in murine preterm placentas post estradiol (E2) exposure. In vitro experiments showed that YTHDC1 promoted trophoblastic cell proliferation and migration, but inhibited cell apoptosis. Mechanistically, E2 was proven to upregulate YTHDC1 expression via retinoid X receptor alpha (RXRA) in trophoblastic cells. Enhanced YTHDC1 expression augmented the translation of RPL37 in an m 6 A-dependent manner by binding to m 6 A-modified RPL37 mRNA and concomitantly promoted the overall translational output. Importantly, administration of siRNA targeting YTHDC1 effectively delayed the progression of preterm delivery. In conclusion, the identified E2/RXRA/YTHDC1/RPL37 axis provides new insights into the epigenetic mechanism underlying ART-associated preterm delivery. The findings offer a potential prognostic biomarker and therapeutic target for preterm delivery.

Source: Cellular and Molecular Life Sciences

DOI: 10.1007/s00018-024-05467-x