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miR-124-3p is a chronic regulator of gene expression after brain injury

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Abstract

Traumatic brain injury (TBI) initiates molecular and cellular pathologies that underlie post-injury morbidities, including hippocampus-related memory decline and epileptogenesis. Non-coding small RNAs are master regulators of gene expression with the potential to affect multiple molecular pathways. To evaluate whether hippocampal gene expression networks are chronically regulated by microRNAs after TBI, we sampled the dentate gyrus of rats with severe TBI induced by lateral fluid-percussion injury 3 months earlier. Ingenuity pathway analysis revealed 30 upregulated miR-124-3p targets, suggesting that miR-124-3p is downregulated post-TBI (z-score = − 5.146, p < 0.05). Droplet digital polymerase chain reaction (ddPCR) and in situ hybridization confirmed the chronic downregulation of miR-124-3p (p < 0.05). Quantitative PCR analysis of two targets, Plp2 and Stat3, indicated that their upregulation correlated with the miR-124-3p downregulation (r = − 0.647, p < 0.05; r = − 0.629, p < 0.05, respectively). Immunohistochemical staining of STAT3 confirmed the increased protein expression. STRING analysis showed that 9 of the 30 miR-124-3p targets belonged to a STAT3 network. Reactome analysis and data mining connected the targets especially to inflammation and signal transduction. L1000CDS2 software revealed drugs (e.g., importazole, trichostatin A, and IKK-16) that could reverse the observed molecular changes. The translational value of our data was emphasized by in situ hybridization showing chronic post-traumatic downregulation of miR-124-3p in the dentate gyrus of TBI patients. Analysis of another brain injury model, status epilepticus, highlighted the fact that chronic downregulation of miR-124 is a common phenomenon after brain injury. Together, our findings indicate that miR-124-3p is a chronic modulator of molecular networks relevant to post-injury hippocampal pathologies in experimental models and in humans.

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Acknowledgements

The research leading to these results received funding from the Academy of Finland (AP) Grant nos. (272249, 273909), Polish National Science Centre Grants (2015/16/T/NZ4/00175 and 2014/15/N/NZ4/04561), as well as from the European Union’s Seventh Framework Programme (FP7/2007–2013) under Grant agreement n°602102 (EPITARGET). We acknowledge the technical support generously provided by Mr. Jarmo Hartikainen, Mrs. Merja Lukkari, and Mr. Jasper Anink.

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Authors and Affiliations

  1. A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211, Kuopio, Finland

    Niina Vuokila, Asla Pitkänen & Noora Puhakka

  2. The Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Str, 02-093, Warsaw, Poland

    Katarzyna Lukasiuk & Anna Maria Bot

  3. Department of (Neuro)pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    Erwin A. van Vliet & Eleonora Aronica

  4. Stichting Epilepsie Instellingen Nederland (SEIN), Amsterdam, The Netherlands

    Eleonora Aronica

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  1. Niina Vuokila
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  4. Erwin A. van Vliet
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Correspondence to Asla Pitkänen or Noora Puhakka.

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Vuokila, N., Lukasiuk, K., Bot, A.M. et al. miR-124-3p is a chronic regulator of gene expression after brain injury. Cell. Mol. Life Sci. 75, 4557–4581 (2018). https://doi.org/10.1007/s00018-018-2911-z

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  • DOI: https://doi.org/10.1007/s00018-018-2911-z

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