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Author Spotlight: Modeling an Aspect of Preeclampsia in Female Mice Using Hypoxic Human Placenta-Derived Small Extracellular Vesicles
Published on: January 26, 2024
A hidden proteome encoded by circRNAs in human placentas: Implications for uncovering preeclampsia pathogenesis
Huanqiang Zhao1,2, Yu Xiong1, Zixiang Zhou1
1The Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.
Insights
Scientists discovered a hidden proteome encoded by circular RNAs (circRNAs) in the human placenta. These circRNA-encoded proteins (CEPs) play roles in placental development and preeclampsia, offering new insights into pregnancy disorders.
Area of Science:
- Genomics and Proteomics
- Molecular Biology
- Reproductive Biology
Background:
- Circular RNAs (circRNAs) encode proteins (CEPs) that act as decoys for their linear counterparts (LEPs).
- The prevalence and function of CEPs in human tissues, particularly the placenta, are largely unknown.
- The placenta's diverse proteome makes it a key site for identifying novel CEPs and their roles in fetal development.
Purpose of the Study:
- To investigate circRNA translation in the human placenta.
- To identify novel CEPs and elucidate their functions in placental development and dysfunction.
- To explore the role of a specific CEP, circPRKCB119aa, in preeclampsia.
Main Methods:
- Utilized multiomics approaches: RNA sequencing, ribosome profiling, and LC-MS/MS.
- Employed bioinformatics and the protein bait hypothesis to analyze CEP functions.
- Investigated circPRKCB119aa's role in preeclampsia using qRT-PCR, Western blotting, immunofluorescence, and phenotypic analyses.
Main Results:
- Identified 528 placental circRNAs bound to ribosomes, with 139 translated into proteins.
- CEPs exhibited structural homology to LEPs but were more stable, hydrophobic, and lower in molecular weight, suggesting a bait function.
- A novel CEP, circPRKCB119aa, was found to enhance trophoblast autophagy by inhibiting PKCβ phosphorylation, contributing to preeclampsia pathogenesis.
Conclusions:
- Discovered a significant circRNA-encoded proteome in the human placenta, providing novel insights into placental development and disorders.
- Identified CEPs as potentially crucial in placental function and associated diseases like preeclampsia.
- Characterized circPRKCB119aa's conserved role in enhancing trophoblast autophagy via protein kinase C (PKC) β inhibition in preeclampsia.
Background:
CircRNA-encoded proteins (CEPs) are emerging as new players in health and disease, and function as baits for the common partners of their cognate linear-spliced RNA encoded proteins (LEPs). However, their prevalence across human tissues and biological roles remain largely unexplored. The placenta is an ideal model for identifying CEPs due to its considerable protein diversity that is required to sustain fetal development during pregnancy. The aim of this study was to evaluate circRNA translation in the human placenta, and the potential roles of the CEPs in placental development and dysfunction.
Methods:
Multiomics approaches, including RNA sequencing, ribosome profiling, and LC-MS/MS analysis, were utilised to identify novel translational events of circRNAs in human placentas. Bioinformatics methods and the protein bait hypothesis were employed to evaluate the roles of these newly discovered CEPs in placentation and associated disorders. The pathogenic role of a recently identified CEP circPRKCB119aa in preeclampsia was investigated through qRT-PCR, Western blotting, immunofluorescence imaging and phenotypic analyses.
Results:
We found that 528 placental circRNAs bound to ribosomes with active translational elongation, and 139 were translated to proteins. The CEPs showed considerable structural homology with their cognate LEPs, but are more stable, hydrophobic and have a lower molecular-weight than the latter, all of which are conducive to their function as baits. On this basis, CEPs are deduced to be closely involved in placental function. Furthermore, we focused on a novel CEP circPRKCB119aa, and illuminated its pathogenic role in preeclampsia; it enhanced trophoblast autophagy by acting as a bait to inhibit phosphorylation of the cognate linear isoform PKCβ.
Conclusions:
We discovered a hidden circRNA-encoded proteome in the human placenta, which offers new insights into the mechanisms underlying placental development, as well as placental disorders such as preeclampsia. Key points A hidden circRNA-encoded proteome in the human placenta was extensively identified and systematically characterised. The circRNA-encoded proteins (CEPs) are potentially related to placental development and associated disorders. A novel conserved CEP circPRKCB119aa enhanced trophoblast autophagy by inhibiting phosphorylation of its cognate linear-spliced isoform protein kinase C (PKC) β in preeclampsia.
