Volume 10 Issue 6
Jun.  2019
Turn off MathJax
Article Contents
Jing Liu, Xu Kong, Mengkai Zhang, Xiao Yang, Xiuqin Xu. RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy[J]. Protein&Cell, 2019, 10(6): 405-416. doi: 10.1007/s13238-018-0578-8
Citation: Jing Liu, Xu Kong, Mengkai Zhang, Xiao Yang, Xiuqin Xu. RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy[J]. Protein&Cell, 2019, 10(6): 405-416. doi: 10.1007/s13238-018-0578-8

RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy

doi: 10.1007/s13238-018-0578-8

This work was supported by the Major State Basic Research Development Program of China (973 Program) (Grant No. 2014CB965101), National Key R&D program of China (Grant No. 2018YFA0107304), and the National Natural Science Foundation of China (NSFC) (Grant Nos. 81670286, 81871744 and 81700255).

  • Received Date: 2018-06-18
  • RNA splicing contributes to a broad spectrum of posttranscriptional gene regulation during normal development, as well as pathological manifestation of heart diseases. However, the functional role and regulation of splicing in heart failure remain poorly understood. RNA binding protein (RBP), a major component of the splicing machinery, is a critical factor in this process. RNA binding motif protein 24 (RBM24) is a tissue-specific RBP which is highly expressed in human and mouse heart. Previous studies demonstrated the functional role of RBM24 in the embryonic heart development. However, the role of RBM24 in postnatal heart development and heart disease has not been investigated. In this paper, using conditional RBM24 knockout mice, we demonstrated that ablation of RBM24 in postnatal heart led to rapidly progressive dilated cardiomyopathy (DCM), heart failure, and postnatal lethality. Global splicing profiling revealed that RBM24 regulated a network of genes related to cardiac function and diseases. Knockout of RBM24 resulted in misregulation of these splicing transitions which contributed to the subsequent development of cardiomyopathy. Notably, our analysis identified RBM24 as a splice factor that determined the splicing switch of a subset of genes in the sacomeric Z-disc complex, including Titin, the major disease gene of DCM and heart failure. Together, this study identifies regulation of RNA splicing by RBM24 as a potent player in remodeling of heart during postnatal development, and provides novel mechanistic insights to the pathogenesis of DCM.
  • loading
  • [1]
    Anderson BR, Granzier HL (2012) Titin-based tension in the cardiac sarcomere:molecular origin and physiological adaptations. Prog Biophys Mol Biol 110(2-3):204-217
    Arimura T, Takeya R, Ishikawa T, Yamano T, Matsuo A, Tatsumi T, Nomura T, Sumimoto H, Kimura A (2013) Dilated cardiomyopathy-associated FHOD3 variant impairs the ability to induce activation of transcription factor serum response factor. Circ J 77(12):2990-2996
    Benz PM, Merkel CJ, Offner K, Abeßer M, Ullrich M, Fischer T, Bayer B, Wagner H, Gambaryan S, Ursitti JA et al (2013) Mena/VASP and alphaⅡ-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy. Cell Commun Signal 11:56
    Beqqali A, Bollen IAE, Rasmussen TB, van den Hoogenhof MM, van Deutekom HWM, Schafer S, Haas J, Meder B, Sørensen KE, van Oort RJ et al (2016) A mutation in the glutamate-rich region of RNA-binding motif protein 20 causes dilated cardiomyopathy through missplicing of titin and impaired Frank-Starling mechanism. Cardiovasc Res 112(1):452-463
    Bienengraeber M, Olson TM, Selivanov VA, Kathmann EC, O'Cochlain F, Gao F, Karger AB, Ballew JD, Hodgson DM, Zingman LV et al (2004) ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Nat Genet 36(4):382-387
    Blech-Hermoni Y, Ladd AN (2013) RNA binding proteins in the regulation of heart development. Int J Biochem Cell Biol 45(11):2467-2478
    Cheng G, Takahashi M, Shunmugavel A, Wallenborn JG, DePaoliRoach AA, Gergs U, Neumann J, Kuppuswamy D, Menick DR, Cooper G (2010) Basis for MAP4 dephosphorylation-related microtubule network densification in pressure overload cardiac hypertrophy. J Biol Chem 285(49):38125-38140
    Cooper TA (2005) Alternative splicing regulation impacts heart development. Cell 120(1):1-2
    Gao C, Ren S, Lee JH, Qiu J, Chapski DJ, Rau CD, Zhou Y, Abdellatif M, Nakano A, Vondriska TM et al (2016) RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure. J Clin Invest 126(1):195-206
    Gregorio CC, Trombitás K, Centner T, Kolmerer B, Stier G, Kunke K, Suzuki K, Obermayr F, Herrmann B, Granzier H et al (1998) The NH2 terminus of titin spans the Z-disc:its interaction with a novel 19-kD ligand (T-cap) is required for sarcomeric integrity. J Cell Biol 143(4):1013-1027
    Guo W, Schafer S, Greaser ML, Radke MH, Liss M, Govindarajan T, Maatz H, Schulz H, Li S, Parrish AM et al (2012) RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat Med 18(5):766-773
    Hallegger M, Llorian M, Smith CW (2010) Alternative splicing:global insights. FEBS J 277(4):856-866
    Kalsotra A, Cooper TA (2011) Functional consequences of developmentally regulated alternative splicing. Nat Rev Genet 12(10):715-729
    Knöll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML, Hayashi T, Shiga N, Yasukawa H, Schaper W et al(2002) The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell 111(7):943-955
    Kong SW, Hu YW, Ho JW, Ikeda S, Polster S, John R, Hall JL, Bisping E, Pieske B, dos Remedios CG et al (2010) Heart failureassociated changes in RNA splicing of sarcomere genes. Circ Cardiovasc Genet 3(2):138-146
    Lara-Pezzi E, Gómez-Salinero J, Gatto A, García-Pavía P (2013) The alternative heart:impact of alternative splicing in heart disease. J Cardiovasc Transl Res 6(6):945-955
    LeMasters KE, Blech-Hermoni Y, Stillwagon SJ, Vajda NA, Ladd AN (2012) Loss of muscleblind-like 1 promotes invasive mesenchyme formation in endocardial cushions by stimulating autocrine TGFbeta3. BMC Dev Biol 12:22
    Lin Y, Tan KT, Liu J, Kong X, Huang Z, Xu XQ (2017) Global profiling of Rbm24 bound RNAs uncovers a multi-tasking RNA binding protein. Int J Biochem Cell Biol 94:10-21
    Liu J, Kong X, Lee YM, Zhang MK, Guo LY, Lin Y, Lim TK, Lin Q, Xu XQ (2017a) Stk38 modulates Rbm24 protein stability to regulate sarcomere assembly in cardiomyocytes. Sci Rep 7:44870
    Liu JS, Fan LL, Zhang H, Liu X, Huang H, Tao LJ, Xia K, Xiang R (2017b) Whole-exome sequencing identifies two novel TTN mutations in Chinese families with dilated cardiomyopathy. Cardiology 136(1):10-14
    Mayr JA, Merkel O, Kohlwein SD, Gebhardt BR, Böhles H, Fötschl U, Koch J, Jaksch M, Lochmüller H, Horváth R et al (2007) Mitochondrial phosphate-carrier deficiency:a novel disorder of oxidative phosphorylation. Am J Hum Genet 80(3):478-484
    Ong SB, Kalkhoran SB, Hernández-Reséndiz S, Samangouei P, Ong SG, Hausenloy DJ (2017) Mitochondrial-shaping proteins in cardiac health and disease-the long and the short of it! Cardiovasc Drugs Ther 31(1):87-107
    Poon KL, Tan KT, Wei YY, Ng CP, Colman A, Korzh V, Xu XQ (2012) RNA-binding protein RBM24 is required for sarcomere assembly and heart contractility. Cardiovasc Res 94(3):418-427
    Purevjav E, Varela J, Morgado M, Kearney DL, Li H, Taylor MD, Arimura T, Moncman CL, McKenna W, Murphy RT et al (2010) Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis. J Am Coll Cardiol 56(18):1493-1502
    Ray D, Kazan H, Cook KB, Weirauch MT, Najafabadi HS, Li X, Gueroussov S, Albu M, Zheng H, Yang A et al (2013) A compendium of RNA-binding motifs for decoding gene regulation. Nature 499(7457):172-177
    Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S et al (2015) Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med 7(270):270-276
    Tayal U, Prasad S, Cook SA (2017) Genetics and genomics of dilated cardiomyopathy and systolic heart failure. Genome Med 9(1):20
    Wang J, Xu N, Feng X, Hou N, Zhang J, Cheng X, Chen Y, Zhang Y, Yang X (2005) Targeted disruption of Smad4 in cardiomyocytes results in cardiac hypertrophy and heart failure. Circ Res 97(8):821-828
    Wei C, Qiu J, Zhou Y, Xue Y, Hu J, Ouyang K, Banerjee I, Zhang C, Chen B, Li H et al (2015) Repression of the central splicing regulator RBFox2 is functionally linked to pressure overloadinduced heart failure. Cell Rep 10:1521-1533
    Weintraub RG, Semsarian C, Macdonald P (2017) Dilated cardiomyopathy. Lancet 16:31713-31715
    Wells QS, Becker JR, Su YR, Mosley JD, Weeke P, D'Aoust L, Ausborn NL, Ramirez AH, Pfotenhauer JP, Naftilan AJ et al(2013) Whole exome sequencing identifies a causal RBM20 mutation in a large pedigree with familial dilated cardiomyopathy. Circ Cardiovasc Genet 6(4):317-326
    Xu XQ, Soo SY, Sun W, Zweigerdt R (2009) Global expression profile of highly enriched cardiomyocytes derived from human embryonic stem cells. Stem Cells 27(9):2163-2174
    Xu XQ, Zweigerdt R, Xu XQ, Zweigerdt R, Soo SY, Ngoh ZX, Tham SC, Wang ST, Graichen R, Davidson B et al (2008) Highly enriched cardiomyocytes from human embryonic stem cells. Cytotherapy 10(4):376-389
    Yang J, Hung L-H, Licht T, Kostin S, Looso M, Khrameeva E, Bindereif A, Schneider A, Braun T (2014) RBM24 is a major regulator of muscle-specific alternative splicing. Dev Cell 31(1):87-99
    Zhang T, Lin Y, Liu J, Zhang ZG, Fu W, Guo LY, Pan L, Kong X, Zhang MK, Lu YH et al (2016) Rbm24 regulates alternative splicing switch in embryonic stem cell cardiac lineage differentiation. Stem Cells 34(7):1776-1789
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索


    Article Metrics

    Article views (818) PDF downloads(493) Cited by()
    Proportional views


    DownLoad:  Full-Size Img  PowerPoint