circZNF827 nucleates a transcription inhibitory complex to balance neuronal differentiation

Anne Kruse Hollensen, Henriette Sylvain Thomsen, Marta Lloret-Llinares, Andreas Bjerregaard Kamstrup, Jacob Malte Jensen, Majbritt Luckmann, Nanna Birkmose, Johan Palmfeldt, Torben Heick Jensen, Thomas B Hansen, Christian Kroun Damgaard

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Abstract

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.

Original languageEnglish
Article numbere58478
JournaleLife
Volume9
Pages (from-to)1-29
Number of pages29
ISSN2050-084X
DOIs
Publication statusPublished - Nov 2020

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