title: Insights into alternative splicing of sarcomeric genes in the heart.
abstract: Driven by rapidly evolving technologies in next-generation sequencing, alternative splicing has emerged as a crucial layer in gene expression, greatly expanding protein diversity and governing complex biological processes in the cardiomyocyte. At the core of cardiac contraction, the physical properties of the sarcomere are carefully orchestrated through alternative splicing to fit the varying demands on the heart. By the recent discovery of RBM20 and RBM24, two major heart and skeletal muscle-restricted splicing factors, it became evident that alternative splicing events in the heart occur in regulated networks rather than in isolated events. Analysis of knockout mice of these splice factors has shed light on the importance of these fundamental processes in the heart. In this review, we discuss recent advances in our understanding of the role and regulation of alternative splicing in the developing and diseased heart, specifically within the sarcomere. Through various examples (titin, myomesin, troponin T, tropomyosin and LDB3) we illustrate how alternative splicing regulates the functional properties of the sarcomere. Finally, we evaluate opportunities and obstacles to modulate alternative splicing in therapeutic approaches for cardiac disease.
authors: Experimental Cardiology, Academic Medical Center, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands.
authors: Cornelis J
authors: CJ
authors: Weeland
authors: Experimental Cardiology, Academic Medical Center, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands.
authors: Maarten M
authors: MM
authors: van den Hoogenhof
authors: Experimental Cardiology, Academic Medical Center, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands.
authors: Abdelaziz
authors: A
authors: Beqqali
authors: Experimental Cardiology, Academic Medical Center, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands. Electronic address: e.e.creemers@amc.uva.nl.
authors: Esther E
authors: EE
authors: Creemers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D017398:Alternative Splicing; D000818:Animals; D064211:Connectin / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006331:Heart Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012518:Sarcomeres / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism; D020107:Troponin T / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D064211:Connectin; D060588:LIM Domain Proteins; C485639:Ldb3 protein, mouse; C584322:RBM20 protein, mouse; D016601:RNA-Binding Proteins; C547648:Rbm24 protein, mouse; D014335:Tropomyosin; D020107:Troponin T; D011494:Protein Kinases; C579730:titin protein, mouse
keywords: Alternative splicing; RBM20; RBM24; Sarcomere; Titin