Integrated analysis of the transcriptome- wide m6A methylome in preeclampsia and healthy control placentas

Abstract

N6-methyladenosine (m6A) is the most prevalent modification in eukaryotic mRNA and potential regulatory functions of m6A have been shown by mapping the RNA m6A modification landscape. m6A modification in active gene regulation manifests itself as altered methylation profiles. The number of reports regarding to the profiling of m6A modification and its potential role in the placenta of preeclampsia (PE) is small. In this work, placental samples were collected from PE and control patients. Expression of m6A-related genes was investigated using quantitative real-time PCR. MeRIP-seq and RNA-seq were performed to detect m6A methylation and mRNA expression profiles. Gene ontology (GO) functional and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses were also conducted to explore the modified genes and their clinical significance. Our findings show that METTL3 and METTL14 were up-regulated in PE. In total, 685 m6A peaks were differentially expressed as determined by MeRIP-seq. Altered peaks of m6A-modified transcripts were primarily associated with nitrogen compound metabolic process, positive regulation of vascular- associated smooth muscle cell migration, and endoplasmic reticulum organisation. The m6A hyper-methylated genes of Wnt/β-catenin signalling pathway, mTOR signalling pathway, and several cancer-related pathways may contribute to PE. We also verified that the significant increase of HSPA1A mRNA and protein expression was regulated by m6A modification, suggesting m6A plays a key role in the regulation of gene expression. Our data provide novel information regarding m6A modification alterations in PE and help our understanding of the pathogenesis of PE.