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Multilateral Bioinformatics Analyses Reveal the Function-Oriented Target Specificities and Recognition of the RNA-Binding Protein SFPQ.

ABSTRACT: RNA-binding proteins (RBPs) recognize consensus sequences and regulate specific target mRNAs. However, large-scale CLIP-seq revealed loose and broad binding of RBPs to larger proportion of expressed mRNAs: e.g. SFPQ binds to >10,000 pre-mRNAs but distinctly regulates <200 target genes during neuronal development. Identification of crucial binding for regulation and rules of target recognition is highly anticipated for systemic understanding of RBP regulations. For a breakthrough solution, we developed a bioinformatical method for CLIP-seq and transcriptome data by adopting iterative hypothesis testing. Essential binding was successfully identified in C-rich sequences close to the 5' splice sites of long introns, which further proposed target recognition mechanism via association between SFPQ and splicing factors during spliceosome assembly. The identified features of functional binding enabled us to predict regulons and also target genes in different species. This multilateral bioinformatics approach facilitates the elucidation of functionality, regulatory mechanism, and regulatory networks of RBPs.

SUBMITTER: Iida K

PROVIDER: S-EPMC7358709 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Multilateral Bioinformatics Analyses Reveal the Function-Oriented Target Specificities and Recognition of the RNA-Binding Protein SFPQ.

Iida Kei K Hagiwara Masatoshi M Takeuchi Akihide A

iScience 20200628 7

RNA-binding proteins (RBPs) recognize consensus sequences and regulate specific target mRNAs. However, large-scale CLIP-seq revealed loose and broad binding of RBPs to larger proportion of expressed mRNAs: e.g. SFPQ binds to >10,000 pre-mRNAs but distinctly regulates <200 target genes during neuronal development. Identification of crucial binding for regulation and rules of target recognition is highly anticipated for systemic understanding of RBP regulations. For a breakthrough solution, we dev ...[more]

PMID: 32659723

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Project description:BackgroundUse of in silico bioinformatics analyses has led to important leads in the complex nature of alcoholism at the genomic, epigenomic, and proteomic level, but has not previously been successfully translated to the development of effective pharmacotherapies. In this study, a bioinformatics approach led to the discovery of neuroimmune pathways as an age-specific druggable target. Minocycline, a neuroimmune modulator, reduced high ethanol (EtOH) drinking in adult, but not adolescent, mice as predicted a priori.MethodsAge and sex-divergent effects in alcohol consumption were quantified in FVB/NJ × C57BL/6J F1 mice given access to 20% alcohol using a 4 h/d, 4-day drinking-in-dark (DID) paradigm. In silico bioinformatics pathway overrepresentation analysis for age-specific effects of alcohol in brain was performed using gene expression data collected in control and DID-treated, adolescent and adult, male mice. Minocycline (50 mg/kg i.p., once daily) or saline alone was tested for an effect on EtOH intake in the F1 and C57BL/6J (B6) mice across both age and gender groups. Effects of minocycline on the pharmacokinetic properties of alcohol were evaluated by comparing the rates of EtOH elimination between the saline- and minocycline-treated F1 and B6 mice.ResultsAge and gender differences in DID consumption were identified. Only males showed a clear developmental increase difference in drinking over time. In silico analyses revealed neuroimmune-related pathways as significantly overrepresented in adult, but not in adolescent, male mice. As predicted, minocycline treatment reduced drinking in adult, but not adolescent, mice. The age effect was present for both genders, and in both the F1 and B6 mice. Minocycline had no effect on the pharmacokinetic elimination of EtOH.ConclusionsOur results are a proof of concept that bioinformatics analysis of brain gene expression can lead to the generation of new hypotheses and a positive translational outcome for individualized pharmacotherapeutic treatment of high alcohol consumption.

Dataset Information

Multilateral Bioinformatics Analyses Reveal the Function-Oriented Target Specificities and Recognition of the RNA-Binding Protein SFPQ.

Publications

Multilateral Bioinformatics Analyses Reveal the Function-Oriented Target Specificities and Recognition of the RNA-Binding Protein SFPQ.

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