title: Chronically dysregulated NOTCH1 interactome in the dentate gyrus after traumatic brain injury.
abstract: Traumatic brain injury (TBI) can result in several dentate gyrus-regulated disabilities. Almost nothing is known about the chronic molecular changes after TBI, and their potential as treatment targets. We hypothesized that chronic transcriptional alterations after TBI are under microRNA (miRNA) control. Expression of miRNAs and their targets in the dentate gyrus was analyzed using microarrays at 3 months after experimental TBI. Of 305 miRNAs present on the miRNA-array, 12 were downregulated (p<0.05). In parallel, 75 of their target genes were upregulated (p<0.05). A bioinformatics analysis of miRNA targets highlighted the dysregulation of the transcription factor NOTCH1 and 39 of its target genes (NOTCH1 interactome). Validation assays confirmed downregulation of miR-139-5p, upregulation of Notch1 and its activated protein, and positive enrichment of NOTCH1 target gene expression. These findings demonstrate that miRNA-based transcriptional regulation can be present at chronic time points after TBI, and highlight the NOTCH1 interactome as one of the mechanisms behind the dentate gyrus pathology-related morbidities.
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Noora
authors.initials: N
authors.lastname: Puhakka
authors.affiliation: The Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Bot
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Vuokila
authors.affiliation: The Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Konrad Jozef
authors.initials: KJ
authors.lastname: Debski
authors.affiliation: The Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Lukasiuk
authors.affiliation: Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Asla
authors.initials: A
authors.lastname: Pitkänen
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D018891:Dentate Gyrus / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D013997:Time Factors; D059467:Transcriptome
chemical_list: D002352:Carrier Proteins; C000600035:MIRN139 microRNA, rat; D035683:MicroRNAs; D051881:Receptor, Notch1