GSE196032
A Hidden Proteome Encoded by circRNAs in Human Placentas: Implications for Uncovering Preeclampsia Pathogenesis
Circular RNAs (circRNAs) are consistently overlooked as translational templates due to computational and experimental limitations. Here, we used multi-omics approaches to identify new translational events of circRNAs in human placentas, and assessed the roles of circRNA-encoded proteins in placentation and associated disorders based on the recently proposed protein bait hypothesis. The combination of placental circRNA sequencing and bioinformatics analysis revealed 219607 circRNAs, of which 35% were identified by the Coding Potential Assessment Tool (CPAT) as having >50% coding probability. Ribosomal profiling further identified 528 novel coding circRNAs, including 217 that coded for microproteins verified by LC-MS/MS. Based on these data, we established the Placental Microprotein Bank (PMB) for coding circRNAs and their coded proteins. These proteins have lower molecular weights, higher stable indices and hydrophobicity compared to the canonical proteins, and potentially link to placental development and adverse pregnancy outcomes such as pre-eclampsia. Furthermore, we identified circPRKCB119aa as a novel preeclampsia-related microprotein that enhanced trophoblast autophagy by inhibiting phosphorylation of its cognate linear-spliced isoform protein kinase C (PKC) ß. In summary, we discovered a hidden circRNA-encoded proteome in the human placenta, which offers new insights into the mechanisms underlying placentation and its disorders such as, but not limited to, preeclampsia. Overall design: Three placentas from the first trimester (6~7 weeks of gestation), second trimester (18~20 weeks of gestation) and third trimester (38~40 weeks of gestation), respectively, were collected for high throughput sequencing of circRNAs.