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Polypyrimidine tract-binding protein blocks miRNA-124 biogenesis to enforce its neuronal-specific expression in the mouse
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posted on 2023-06-09, 18:04 authored by Kyu-Hyeon Yeom, Simon MitchellSimon Mitchell, Anthony J Linares, Sika Zheng, Chia-Ho Lin, Xiao-Jun Wang, Alexander Hoffmann, Douglas L BlackMicroRNA (miRNA)-124 is expressed in neurons, where it represses genes inhibitory for neuronal differentiation, including the RNA binding protein PTBP1. PTBP1 maintains nonneuronal splicing patterns of mRNAs that switch to neuronal isoforms upon neuronal differentiation. We find that primary (pri)-miR-124-1 is expressed in mouse embryonic stem cells where mature miR-124 is absent. PTBP1 binds to this precursor RNA upstream of the miRNA stem–loop to inhibit mature miR-124 expression in vivo and DROSHA cleavage of pri-miR-124-1 in vitro. This function for PTBP1 in repressing miR-124 biogenesis defines an additional regulatory loop in the already intricate interplay between these two molecules. Applying mathematical modeling to examine the dynamics of this regulation, we find that the pool of pri-miR-124 whose maturation is blocked by PTBP1 creates a robust and self-reinforcing transition in gene expression as PTBP1 is depleted during early neuronal differentiation. While interlocking regulatory loops are often found between miRNAs and transcriptional regulators, our results indicate that miRNA targeting of posttranscriptional regulators also reinforces developmental decisions. Notably, induction of neuronal differentiation observed upon PTBP1 knockdown likely results from direct derepression of miR-124, in addition to indirect effects previously described.
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Publication status
- Published
Journal
Proceedings of the National Academy of SciencesISSN
0027-8424Publisher
National Academy of SciencesExternal DOI
Issue
47Volume
115Article number
E11061-E11070Department affiliated with
- Clinical and Experimental Medicine Publications
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- No
Peer reviewed?
- Yes
Legacy Posted Date
2019-06-17Usage metrics
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