SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy
Alternative mRNA splicing is a fundamental process to increase the versatility of the genome. In humans, cardiac mRNA splicing is involved in the pathophysiology of heart failure. Mutations in the splicing factor RNA binding motif protein 20 (RBM20) cause severe forms of cardiomyopathy. To identify...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-02-01
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| Series: | Genomics, Proteomics & Bioinformatics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1672022921001467 |
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| author | Jes-Niels Boeckel Maximilian Möbius-Winkler Marion Müller Sabine Rebs Nicole Eger Laura Schoppe Rewati Tappu Karoline E. Kokot Jasmin M. Kneuer Susanne Gaul Diana M. Bordalo Alan Lai Jan Haas Mahsa Ghanbari Philipp Drewe-Boss Martin Liss Hugo A. Katus Uwe Ohler Michael Gotthardt Ulrich Laufs Katrin Streckfuss-Bömeke Benjamin Meder |
| author_facet | Jes-Niels Boeckel Maximilian Möbius-Winkler Marion Müller Sabine Rebs Nicole Eger Laura Schoppe Rewati Tappu Karoline E. Kokot Jasmin M. Kneuer Susanne Gaul Diana M. Bordalo Alan Lai Jan Haas Mahsa Ghanbari Philipp Drewe-Boss Martin Liss Hugo A. Katus Uwe Ohler Michael Gotthardt Ulrich Laufs Katrin Streckfuss-Bömeke Benjamin Meder |
| author_sort | Jes-Niels Boeckel |
| collection | DOAJ |
| description | Alternative mRNA splicing is a fundamental process to increase the versatility of the genome. In humans, cardiac mRNA splicing is involved in the pathophysiology of heart failure. Mutations in the splicing factor RNA binding motif protein 20 (RBM20) cause severe forms of cardiomyopathy. To identify novel cardiomyopathy-associated splicing factors, RNA-seq and tissue-enrichment analyses were performed, which identified up-regulated expression of Sam68-Like mammalian protein 2 (SLM2) in the left ventricle of dilated cardiomyopathy (DCM) patients. In the human heart, SLM2 binds to important transcripts of sarcomere constituents, such as those encoding myosin light chain 2 (MYL2), troponin I3 (TNNI3), troponin T2 (TNNT2), tropomyosin 1/2 (TPM1/2), and titin (TTN). Mechanistically, SLM2 mediates intron retention, prevents exon exclusion, and thereby mediates alternative splicing of the mRNA regions encoding the variable proline-, glutamate-, valine-, and lysine-rich (PEVK) domain and another part of the I-band region of titin. In summary, SLM2 is a novel cardiac splicing regulator with essential functions for maintaining cardiomyocyte integrity by binding to and processing the mRNAs of essential cardiac constituents such as titin. |
| first_indexed | 2024-03-08T17:54:01Z |
| format | Article |
| id | doaj.art-1a62d499b1c84c03a1e970a9381d3d3a |
| institution | Directory Open Access Journal |
| issn | 1672-0229 |
| language | English |
| last_indexed | 2024-03-08T17:54:01Z |
| publishDate | 2022-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Genomics, Proteomics & Bioinformatics |
| spelling | doaj.art-1a62d499b1c84c03a1e970a9381d3d3a2024-01-02T06:01:37ZengElsevierGenomics, Proteomics & Bioinformatics1672-02292022-02-01201129146SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated CardiomyopathyJes-Niels Boeckel0Maximilian Möbius-Winkler1Marion Müller2Sabine Rebs3Nicole Eger4Laura Schoppe5Rewati Tappu6Karoline E. Kokot7Jasmin M. Kneuer8Susanne Gaul9Diana M. Bordalo10Alan Lai11Jan Haas12Mahsa Ghanbari13Philipp Drewe-Boss14Martin Liss15Hugo A. Katus16Uwe Ohler17Michael Gotthardt18Ulrich Laufs19Katrin Streckfuss-Bömeke20Benjamin Meder21Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, D-69120 Heidelberg, Germany; Klinik und Poliklinik für Kardiologie, Universitätskrankenhaus Leipzig, D-04103 Leipzig, GermanyKlinik und Poliklinik für Kardiologie, Universitätskrankenhaus Leipzig, D-04103 Leipzig, GermanyDepartment of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, D-69120 Heidelberg, Germany; German Center for Cardiovascular Research (DZHK), Partner site Heidelberg, D-69120 Heidelberg, Germany; Clinic for General and Interventional Cardiology/Angiology, Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum, D-32545 Bad Oeynhausen, GermanyDepartment of Cardiology and Pneumology, University Hospital, Georg-August University Goettingen, D-37075 Goettingen, Germany; German Center for Cardiovascular Research (DZHK), Partner site Goettingen, D-37075 Goettingen, GermanyDepartment of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, D-69120 Heidelberg, GermanyDepartment of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, D-69120 Heidelberg, GermanyDepartment of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, D-69120 Heidelberg, GermanyKlinik und Poliklinik für Kardiologie, Universitätskrankenhaus Leipzig, D-04103 Leipzig, GermanyKlinik und Poliklinik für Kardiologie, Universitätskrankenhaus Leipzig, D-04103 Leipzig, GermanyKlinik und Poliklinik für Kardiologie, Universitätskrankenhaus Leipzig, D-04103 Leipzig, GermanyDepartment of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, D-69120 Heidelberg, Germany; German Center for Cardiovascular Research (DZHK), Partner site Heidelberg, D-69120 Heidelberg, GermanyDepartment of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, D-69120 Heidelberg, Germany; German Center for Cardiovascular Research (DZHK), Partner site Heidelberg, D-69120 Heidelberg, GermanyDepartment of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, D-69120 Heidelberg, Germany; German Center for Cardiovascular Research (DZHK), Partner site Heidelberg, D-69120 Heidelberg, GermanyBerlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, D-10115 Berlin, Germany; Institute of Biology, Humboldt Universität zu Berlin, D-10099 Berlin, GermanyBerlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, D-10115 Berlin, Germany; Institute of Biology, Humboldt Universität zu Berlin, D-10099 Berlin, GermanyNeuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, D-13092 Berlin, Germany; German Center for Cardiovascular Research (DZHK), Partner site Berlin, D-10117 Berlin, GermanyDepartment of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, D-69120 Heidelberg, Germany; German Center for Cardiovascular Research (DZHK), Partner site Heidelberg, D-69120 Heidelberg, GermanyBerlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, D-10115 Berlin, Germany; Institute of Biology, Humboldt Universität zu Berlin, D-10099 Berlin, GermanyNeuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, D-13092 Berlin, Germany; German Center for Cardiovascular Research (DZHK), Partner site Berlin, D-10117 Berlin, GermanyKlinik und Poliklinik für Kardiologie, Universitätskrankenhaus Leipzig, D-04103 Leipzig, GermanyDepartment of Cardiology and Pneumology, University Hospital, Georg-August University Goettingen, D-37075 Goettingen, Germany; German Center for Cardiovascular Research (DZHK), Partner site Goettingen, D-37075 Goettingen, GermanyDepartment of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, D-69120 Heidelberg, Germany; German Center for Cardiovascular Research (DZHK), Partner site Heidelberg, D-69120 Heidelberg, Germany; Stanford Genome Technology Center, Department of Genetics, Stanford Medical School, Palo Alto, CA 94304, USA; Corresponding author.Alternative mRNA splicing is a fundamental process to increase the versatility of the genome. In humans, cardiac mRNA splicing is involved in the pathophysiology of heart failure. Mutations in the splicing factor RNA binding motif protein 20 (RBM20) cause severe forms of cardiomyopathy. To identify novel cardiomyopathy-associated splicing factors, RNA-seq and tissue-enrichment analyses were performed, which identified up-regulated expression of Sam68-Like mammalian protein 2 (SLM2) in the left ventricle of dilated cardiomyopathy (DCM) patients. In the human heart, SLM2 binds to important transcripts of sarcomere constituents, such as those encoding myosin light chain 2 (MYL2), troponin I3 (TNNI3), troponin T2 (TNNT2), tropomyosin 1/2 (TPM1/2), and titin (TTN). Mechanistically, SLM2 mediates intron retention, prevents exon exclusion, and thereby mediates alternative splicing of the mRNA regions encoding the variable proline-, glutamate-, valine-, and lysine-rich (PEVK) domain and another part of the I-band region of titin. In summary, SLM2 is a novel cardiac splicing regulator with essential functions for maintaining cardiomyocyte integrity by binding to and processing the mRNAs of essential cardiac constituents such as titin.http://www.sciencedirect.com/science/article/pii/S1672022921001467SplicingTitinDilated cardiomyopathyKHDRBS3SLM2 |
| spellingShingle | Jes-Niels Boeckel Maximilian Möbius-Winkler Marion Müller Sabine Rebs Nicole Eger Laura Schoppe Rewati Tappu Karoline E. Kokot Jasmin M. Kneuer Susanne Gaul Diana M. Bordalo Alan Lai Jan Haas Mahsa Ghanbari Philipp Drewe-Boss Martin Liss Hugo A. Katus Uwe Ohler Michael Gotthardt Ulrich Laufs Katrin Streckfuss-Bömeke Benjamin Meder SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy Genomics, Proteomics & Bioinformatics Splicing Titin Dilated cardiomyopathy KHDRBS3 SLM2 |
| title | SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy |
| title_full | SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy |
| title_fullStr | SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy |
| title_full_unstemmed | SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy |
| title_short | SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy |
| title_sort | slm2 is a novel cardiac splicing factor involved in heart failure due to dilated cardiomyopathy |
| topic | Splicing Titin Dilated cardiomyopathy KHDRBS3 SLM2 |
| url | http://www.sciencedirect.com/science/article/pii/S1672022921001467 |
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