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A Computational Analysis of Alternative Splicing across Mammalian Tissues Reveals Circadian and Ultradian Rhythms in Splicing Events

1
Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 10117 Berlin, Germany
2
Medical Department of Hematology, Oncology and Tumor Immunology, and Molekulares Krebsforschungszentrum (MKFZ), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(16), 3977; https://doi.org/10.3390/ijms20163977
Received: 9 July 2019 / Revised: 3 August 2019 / Accepted: 10 August 2019 / Published: 15 August 2019
(This article belongs to the Section Molecular Informatics)
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Abstract

Mounting evidence points to a role of the circadian clock in the temporal regulation of post-transcriptional processes in mammals, including alternative splicing (AS). In this study, we carried out a computational analysis of circadian and ultradian rhythms on the transcriptome level to characterise the landscape of rhythmic AS events in published datasets covering 76 tissues from mouse and olive baboon. Splicing-related genes with 24-h rhythmic expression patterns showed a bimodal distribution of peak phases across tissues and species, indicating that they might be controlled by the circadian clock. On the output level, we identified putative oscillating AS events in murine microarray data and pairs of differentially rhythmic splice isoforms of the same gene in baboon RNA-seq data that peaked at opposing times of the day and included oncogenes and tumour suppressors. We further explored these findings using a new circadian RNA-seq dataset of human colorectal cancer cell lines. Rhythmic isoform expression patterns differed between the primary tumour and the metastatic cell line and were associated with cancer-related biological processes, indicating a functional role of rhythmic AS that might be implicated in tumour progression. Our data shows that rhythmic AS events are widespread across mammalian tissues and might contribute to a temporal diversification of the proteome. View Full-Text
Keywords: circadian rhythms; ultradian rhythms; alternative splicing; splicing factors; splice isoforms; cancer; tumour progression circadian rhythms; ultradian rhythms; alternative splicing; splicing factors; splice isoforms; cancer; tumour progression
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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El-Athman, R.; Knezevic, D.; Fuhr, L.; Relógio, A. A Computational Analysis of Alternative Splicing across Mammalian Tissues Reveals Circadian and Ultradian Rhythms in Splicing Events. Int. J. Mol. Sci. 2019, 20, 3977.

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