Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
Andreas Bjerregaard Kamstrup
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
Jacob Malte Jensen
Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
Majbritt Luckmann
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
Nanna Birkmose
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
Johan Palmfeldt
Department of Clinical Medicine, Research Unit for Molecular Medicine, Aarhus University, Aarhus, Denmark
Circular RNAs are important for many cellular processes but their mechanisms of action remain poorly understood. Here, we map circRNA inventories of mouse embryonic stem cells, neuronal progenitor cells and differentiated neurons and identify hundreds of highly expressed circRNAs. By screening several candidate circRNAs for a potential function in neuronal differentiation, we find that circZNF827 represses expression of key neuronal markers, suggesting that this molecule negatively regulates neuronal differentiation. Among 760 tested genes linked to known neuronal pathways, knockdown of circZNF827 deregulates expression of numerous genes including nerve growth factor receptor (NGFR), which becomes transcriptionally upregulated to enhance NGF signaling. We identify a circZNF827-nucleated transcription-repressive complex containing hnRNP-K/L proteins and show that knockdown of these factors strongly augments NGFR regulation. Finally, we show that the ZNF827 protein is part of the mRNP complex, suggesting a functional co-evolution of a circRNA and the protein encoded by its linear pre-mRNA host.
