Epitranscriptomic profiling in human placenta: N6-methyladenosine modification at the 5′-untranslated region is related to fetal growth and preeclampsia

Intracellular mRNA levels are not always proportional to their respective protein levels, especially in the placenta. This discrepancy may be attributed to various factors including post-transcriptional regulation, such as mRNA methylation (N6-methyladenosine: m(6)A). Here, we conducted a comprehensive m(6)A analysis of human placental tissue from neonates with various birth weights to clarify the involvement of m(6)A in placental biology. The augmented m(6)A levels at the 5'-untranslated region (UTR) in mRNAs of small-for-date placenta samples were dominant compared to reduction of m(6)A levels, whereas a decrease in m(6)A in the vicinity of stop codons was common in heavy-for-date placenta samples. Notably, most of these genes showed similar expression levels between the different birth weight categories. In particular, preeclampsia placenta samples showed consistently upregulated SMPD1 protein levels and increased m(6)A at 5'-UTR but did not show increased mRNA levels. Mutagenesis of adenosines at 5'-UTR of SMPD1 mRNAs actually decreased protein levels in luciferase assay. Collectively, our findings suggest that m(6)A both at the 5'-UTR and in the vicinity of stop codon in placental mRNA may play important roles in fetal growth and disease.