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 bin...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 chain2(MYL2),troponin 13(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.展开更多
基金supported by grants from the Deutsches Zentrum für Herz-Kreislauf-Forschung(German Center for Cardiovascular Research,DZHK,Germany)the German Ministry of Education and Research(Grant No.FKZ 031L0075B,Ca RNAtion,Germany)+4 种基金the Informatics for Life(Klaus Tschira Foundation,Germany)the Faculty of Medicine of the Leipzig University to MMWthe Dr.Marija Orlovic Stiftung(Grant No.T0395/35973/2020,Germany)to JNBthe European Union(Grant No.FP7 Best Ageing,Europe)supported by an excellence fellowship of the Else Kr?ner Fresenius Foundation(Germany)。
文摘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 chain2(MYL2),troponin 13(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.
