The RNA landscape of the human placenta in health and disease

The placenta is the interface between mother and fetus and inadequate function contributes to short and long-term ill-health. The placenta is absent from most large-scale RNA-Seq datasets. We therefore analyzed long and small RNAs (~102 and 20 million reads per sample respectively) from 302 human placentas, including 94 cases of preeclampsia (PE) and 56 cases of fetal growth restriction (FGR). The placental transcriptome has the seventh lowest complexity of 50 human tissues: 271 genes accounted for 50% of all reads. We identified multiple circular RNAs and validated 6 of these by Sanger sequencing across the back-splice junction. Using large-scale mass spectrometry datasets, we found strong evidence of peptides produced by translation of two circular RNAs. We also identified novel piRNAs which were clustered on Chr1 and Chr14. PE and FGR were associated with multiple and overlapping differences in mRNA, lincRNA and circRNA but fewer consistent differences in small RNAs. Of the three protein coding genes differentially expressed in both PE and FGR, one encoded a secreted protein FSTL3, (follistatin-like 3). Elevated serum levels of FSTL3 in pregnant women were predictive of subsequent PE and FGR. To aid visualization of our placenta transcriptome data, we developed a web application (https://www.obgyn.cam.ac.uk/placentome/)This work was supported by the Medical Research Council (United Kingdom; G1100221 and MR/K021133/1) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (Women’s Health theme). P.D.W.K. and S.R. were supported by the Medical Research Council (United Kingdom; MC_UU_00002/13 and MC_UU_00002/10, respectively)