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CircZNF827 nucleates a transcription inhibitory complex to balance neuronal differentiation.

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.

SUBMITTER: Hollensen AK

PROVIDER: S-EPMC7657652 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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<i>circZNF827</i> nucleates a transcription inhibitory complex to balance neuronal differentiation.

Hollensen Anne Kruse AK Thomsen Henriette Sylvain HS Lloret-Llinares Marta M Kamstrup Andreas Bjerregaard AB Jensen Jacob Malte JM Luckmann Majbritt M Birkmose Nanna N Palmfeldt Johan J Jensen Torben Heick TH Hansen Thomas B TB Damgaard Christian Kroun CK

eLife 20201111

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 <i>circZNF827</i> represses expression of key neuronal markers, suggesting that this molecule negatively regula ...[more]

PMID: 33174841

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Project description:BackgroundThe octapeptide Angiotensin II is a key hormone that acts via its receptor AT1R in the brainstem to modulate the blood pressure control circuits and thus plays a central role in the cardiac and respiratory homeostasis. This modulation occurs via activation of a complex network of signaling proteins and transcription factors, leading to changes in levels of key genes and proteins. AT1R initiated activity in the nucleus tractus solitarius (NTS), which regulates blood pressure, has been the subject of extensive molecular analysis. But the adaptive network interactions in the NTS response to AT1R, plausibly related to the development of hypertension, are not understood.ResultsWe developed and analyzed a mathematical model of AT1R-activated signaling kinases and a downstream gene regulatory network, with structural basis in our transcriptomic data analysis and literature. To our knowledge, our report presents the first computational model of this key regulatory network. Our simulations and analysis reveal a dynamic balance among distinct dimers of the AP-1 family of transcription factors. We investigated the robustness of this behavior to simultaneous perturbations in the network parameters using a novel multivariate approach that integrates global sensitivity analysis with decision-tree methods. Our analysis implicates a subset of Fos and Jun dependent mechanisms, with dynamic sensitivities shifting from Fos-regulating kinase (FRK)-mediated processes to those downstream of c-Jun N-terminal kinase (JNK). Decision-tree analysis indicated that while there may be a large combinatorial functional space feasible for neuronal states and parameters, the network behavior is constrained to a small set of AP-1 response profiles. Many of the paths through the combinatorial parameter space lead to a dynamic balance of AP-1 dimer forms, yielding a robust AP-1 response counteracting the biological variability.ConclusionsBased on the simulation and analysis results, we demonstrate that a dynamic balance among distinct dimers of the AP-1 family of transcription factors underlies the robust activation of neuronal gene expression in the NTS response to AT1R activation. Such a differential sensitivity to limited set of mechanisms is likely to underlie the stable homeostatic physiological response.

Dataset Information

CircZNF827 nucleates a transcription inhibitory complex to balance neuronal differentiation.

Publications

<i>circZNF827</i> nucleates a transcription inhibitory complex to balance neuronal differentiation.

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