Loss of RNA-Binding Protein Sfpq Causes Long-Gene Transcriptopathy in Skeletal Muscle and Severe Muscle Mass Reduction with Metabolic Myopathy
Summary: Growing evidences are suggesting that extra-long genes in mammals are vulnerable for full-gene length transcription and dysregulation of long genes is a mechanism underlying human genetic disorders. How long-distance transcription is achieved is a fundamental question to be elucidated. In p...
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Elsevier
2019-03-01
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| Series: | iScience |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004219300574 |
| _version_ | 1811235019920769024 |
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| author | Motoyasu Hosokawa Akihide Takeuchi Jun Tanihata Kei Iida Shin'ichi Takeda Masatoshi Hagiwara |
| author_facet | Motoyasu Hosokawa Akihide Takeuchi Jun Tanihata Kei Iida Shin'ichi Takeda Masatoshi Hagiwara |
| author_sort | Motoyasu Hosokawa |
| collection | DOAJ |
| description | Summary: Growing evidences are suggesting that extra-long genes in mammals are vulnerable for full-gene length transcription and dysregulation of long genes is a mechanism underlying human genetic disorders. How long-distance transcription is achieved is a fundamental question to be elucidated. In previous study, we had discovered that RNA-binding protein SFPQ preferentially binds to long pre-mRNAs and specifically regulates the cluster of neuronal genes >100 kbp. Here we investigated the roles of SFPQ for long gene expression, target specificities, and also physiological functions in skeletal muscle. Loss of Sfpq selectively downregulated genes >100 kbp including Dystrophin, which is 2.26 Mbp in length. Sfpq knockout (KO) mice showed progressive muscle mass reduction and metabolic myopathy characterized by glycogen accumulation and decreased abundance of mitochondrial oxidative phosphorylation complexes. Functional clustering analysis identified energy metabolism pathway genes as SFPQ's targets. These findings indicate target gene specificities and tissue-specific physiological functions of SFPQ in skeletal muscle. : Molecular Biology; Molecular Mechanism of Gene Regulation; Pathophysiology Subject Areas: Molecular Biology, Molecular Mechanism of Gene Regulation, Pathophysiology |
| first_indexed | 2024-04-12T11:45:11Z |
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| id | doaj.art-82ff33834e4d41dabc407e2f4f782a6d |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-12T11:45:11Z |
| publishDate | 2019-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-82ff33834e4d41dabc407e2f4f782a6d2022-12-22T03:34:23ZengElsevieriScience2589-00422019-03-0113229242Loss of RNA-Binding Protein Sfpq Causes Long-Gene Transcriptopathy in Skeletal Muscle and Severe Muscle Mass Reduction with Metabolic MyopathyMotoyasu Hosokawa0Akihide Takeuchi1Jun Tanihata2Kei Iida3Shin'ichi Takeda4Masatoshi Hagiwara5Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, JapanDepartment of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Corresponding authorDepartment of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan; Department of Cell Physiology, The Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, JapanMedical Research Support Center, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, JapanDepartment of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, JapanDepartment of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Corresponding authorSummary: Growing evidences are suggesting that extra-long genes in mammals are vulnerable for full-gene length transcription and dysregulation of long genes is a mechanism underlying human genetic disorders. How long-distance transcription is achieved is a fundamental question to be elucidated. In previous study, we had discovered that RNA-binding protein SFPQ preferentially binds to long pre-mRNAs and specifically regulates the cluster of neuronal genes >100 kbp. Here we investigated the roles of SFPQ for long gene expression, target specificities, and also physiological functions in skeletal muscle. Loss of Sfpq selectively downregulated genes >100 kbp including Dystrophin, which is 2.26 Mbp in length. Sfpq knockout (KO) mice showed progressive muscle mass reduction and metabolic myopathy characterized by glycogen accumulation and decreased abundance of mitochondrial oxidative phosphorylation complexes. Functional clustering analysis identified energy metabolism pathway genes as SFPQ's targets. These findings indicate target gene specificities and tissue-specific physiological functions of SFPQ in skeletal muscle. : Molecular Biology; Molecular Mechanism of Gene Regulation; Pathophysiology Subject Areas: Molecular Biology, Molecular Mechanism of Gene Regulation, Pathophysiologyhttp://www.sciencedirect.com/science/article/pii/S2589004219300574 |
| spellingShingle | Motoyasu Hosokawa Akihide Takeuchi Jun Tanihata Kei Iida Shin'ichi Takeda Masatoshi Hagiwara Loss of RNA-Binding Protein Sfpq Causes Long-Gene Transcriptopathy in Skeletal Muscle and Severe Muscle Mass Reduction with Metabolic Myopathy iScience |
| title | Loss of RNA-Binding Protein Sfpq Causes Long-Gene Transcriptopathy in Skeletal Muscle and Severe Muscle Mass Reduction with Metabolic Myopathy |
| title_full | Loss of RNA-Binding Protein Sfpq Causes Long-Gene Transcriptopathy in Skeletal Muscle and Severe Muscle Mass Reduction with Metabolic Myopathy |
| title_fullStr | Loss of RNA-Binding Protein Sfpq Causes Long-Gene Transcriptopathy in Skeletal Muscle and Severe Muscle Mass Reduction with Metabolic Myopathy |
| title_full_unstemmed | Loss of RNA-Binding Protein Sfpq Causes Long-Gene Transcriptopathy in Skeletal Muscle and Severe Muscle Mass Reduction with Metabolic Myopathy |
| title_short | Loss of RNA-Binding Protein Sfpq Causes Long-Gene Transcriptopathy in Skeletal Muscle and Severe Muscle Mass Reduction with Metabolic Myopathy |
| title_sort | loss of rna binding protein sfpq causes long gene transcriptopathy in skeletal muscle and severe muscle mass reduction with metabolic myopathy |
| url | http://www.sciencedirect.com/science/article/pii/S2589004219300574 |
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