期刊
GENOMICS PROTEOMICS & BIOINFORMATICS
卷 20, 期 1, 页码 129-146出版社
ELSEVIER
DOI: 10.1016/j.gpb.2021.01.006
关键词
Splicing; Titin; Dilated cardiomyopathy; KHDRBS3; SLM2
资金
- Deutsches Zentrum fur Herz-Kreislauf-Forschung (German Center for Cardiovascular Research, DZHK, Germany)
- German Ministry of Education and Research [T0395/35973/2020]
- Informatics for Life (Klaus Tschira Foundation, Germany)
- Faculty of Medicine of the Leipzig University
- Dr. Marija Orlovic Stiftung [FP7]
- European Union
- excellence fellowship of the Else Kroner Fresenius Foundation (Germany)
- [FKZ 031L0075B]
Alternative mRNA splicing is a fundamental process in increasing the versatility of the genome. In this study, SLM2 is identified as a novel cardiac splicing regulator that plays an essential role in maintaining cardiomyocyte integrity.
Alternative mRNA splicing is a fundamental process to increase the versatility of the gen-ome. In humans, cardiac mRNA splicing is involved in the pathophysiology of heart failure. Mutationsin 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 anal-yses 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 medi-ates 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.
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