Browse > Article
http://dx.doi.org/10.14348/molcells.2014.2337

Pressure-Overload Cardiac Hypertrophy Is Associated with Distinct Alternative Splicing Due to Altered Expression of Splicing Factors  

Kim, Taeyong (School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology)
Kim, Jin Ock (School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology)
Oh, Jae Gyun (Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai)
Hong, Seong-Eui (School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology)
Kim, Do Han (School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology)
Publication Information
Molecules and Cells / v.37, no.1, 2014 , pp. 81-87 More about this Journal
Abstract
Chronic pressure-overload cardiac hypertrophy is associated with an increased risk of morbidity/mortality, largely due to maladaptive remodeling and dilatation that progresses to dilated cardiomyopathy. Alternative splicing is an important biological mechanism that generates proteomic complexity and diversity. The recent development of next-generation RNA sequencing has improved our understanding of the qualitative signatures associated with alternative splicing in various biological conditions. However, the role of alternative splicing in cardiac hypertrophy is yet unknown. The present study employed RNA-Seq and a bioinformatic approach to detect the RNA splicing regulatory elements involved in alternative splicing during pressure-overload cardiac hypertrophy. We found GC-rich exonic motifs that regulate intron retention in 5' UTRs and AT-rich exonic motifs that are involved in exclusion of the AT-rich elements that cause mRNA instability in 3' UTRs. We also identified motifs in the intronic regions involved in exon exclusion and inclusion, which predicted splicing factors that bind to these motifs. We found, through Western blotting, that the expression levels of three splicing factors, ESRP1, PTB and SF2/ASF, were significantly altered during cardiac hypertrophy. Collectively, the present results suggest that chronic pressure-overload hypertrophy is closely associated with distinct alternative splicing due to altered expression of splicing factors.
Keywords
cardiac hypertrophy; ESRP1; PTB; RNA-Seq; SF2/ASF; splicing factor;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Beltran, M., Puig, I., Pena, C., Garcia, J.M., Alvarez, A.B., Pena, R., Bonilla, F., and de Herreros, A.G. (2008). A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. Genes Dev. 22, 756-769.   DOI   ScienceOn
2 Ames, E.G., Lawson, M.J., Mackey, A.J., and Holmes, J.W. (2013). Sequencing of mRNA identifies re-expression of fetal splice variants in cardiac hypertrophy. J. Mol. Cell Cardiol. 62, 99-107.   DOI   ScienceOn
3 Arrisi-Mercado, P., Romano, M., Muro, A.F., and Baralle, F.E. (2004). An exonic splicing enhancer offsets the atypical GU-rich 3′ splice site of human apolipoprotein A-II exon 3. J. Biol. Chem. 279, 39331-39339.   DOI   ScienceOn
4 Barreau, C., Paillard, L., and Osborne, H.B. (2005). AU-rich elements and associated factors: are there unifying principles? Nucleic Acids Res. 33, 7138-7150.   DOI   ScienceOn
5 Cha, H., Kim, J.M., Oh, J.G., Jeong, M.H., Park, C.S., Park, J., Jeong, H.J., Park, B.K., Lee, Y.H., Jeong, D., et al. (2008). PICOT is a critical regulator of cardiac hypertrophy and cardiomyocyte contractility. J. Mol. Cell Cardiol. 45, 796-803.   DOI   ScienceOn
6 Fairbrother, W.G., Yeh, R.F., Sharp, P.A., and Burge, C.B. (2002). Predictive identification of exonic splicing enhancers in human genes. Science 297, 1007-1013.   DOI   ScienceOn
7 Dittmar, K.A., Jiang, P., Park, J.W., Amirikian, K., Wan, J., Shen, S., Xing, Y., and Carstens, R.P. (2012). Genome-wide determination of a broad ESRP-regulated posttranscriptional network by high-throughput sequencing. Mol. Cell. Biol. 32, 1468-1482.   DOI   ScienceOn
8 Erkelenz, S., Mueller, W.F., Evans, M.S., Busch, A., Schoneweis, K., Hertel, K.J., and Schaal, H. (2013). Position-dependent splicing activation and repression by SR and hnRNP proteins rely on common mechanisms. RNA 19, 96-102.   DOI
9 Eswaran, J., Horvath, A., Godbole, S., Reddy, S.D., Mudvari, P., Ohshiro, K., Cyanam, D., Nair, S., Fuqua, S.A., Polyak, K., et al. (2013). RNA sequencing of cancer reveals novel splicing alterations. Sci. Rep. 3, 1689.   DOI
10 Galante, P.A., Sakabe, N.J., Kirschbaum-Slager, N., and de Souza, S.J. (2004). Detection and evaluation of intron retention events in the human transcriptome. RNA 10, 757-765.   DOI
11 Gooding, C., Edge, C., Lorenz, M., Coelho, M.B., Winters, M., Kaminski, C.F., Cherny, D., Eperon, I.C., and Smith, C.W. (2013). MBNL1 and PTB cooperate to repress splicing of Tpm1 exon 3. Nucleic Acids Res. 41, 4765-4782.   DOI   ScienceOn
12 Hong, S.E., Park, I., Cha, H., Rho, S.H., Park, W.J., Cho, C., and Kim, D.H. (2008). Identification of mouse heart transcriptomic network sensitive to various heart diseases. Biotechnol. J. 3, 648-658.   DOI   ScienceOn
13 Hastings, M.L., Wilson, C.M., and Munroe, S.H. (2001). A purinerich intronic element enhances alternative splicing of thyroid hormone receptor mRNA. RNA 7, 859-874.   DOI   ScienceOn
14 Hirose, T., Ideue, T., Nagai, M., Hagiwara, M., Shu, M.D., and Steitz, J.A. (2006). A spliceosomal intron binding protein, IBP160, links position-dependent assembly of intron-encoded box C/D snoRNP to pre-mRNA splicing. Mol. Cell 23, 673-684.   DOI   ScienceOn
15 Kalsotra, A., Wang, K., Li, P.F., and Cooper, T.A. (2010). MicroRNAs coordinate an alternative splicing network during mouse postnatal heart development. Genes Dev. 24, 653-658.   DOI   ScienceOn
16 Huh, G.S., and Hynes, R.O. (1994). Regulation of alternative premRNA splicing by a novel repeated hexanucleotide element. Genes Dev. 8, 1561-1574.   DOI   ScienceOn
17 Kalari, K.R., Rossell, D., Necela, B.M., Asmann, Y.W., Nair, A., Baheti, S., Kachergus, J.M., Younkin, C.S., Baker, T., Carr, J.M., et al. (2012). Deep sequence analysis of non-small cell lung cancer: integrated analysis of gene expression, alternative splicing, and single nucleotide variations in lung adenocarcinomas with and without oncogenic KRAS mutations. Front Oncol. 2, 12.
18 Kim, E., Goren, A., and Ast, G. (2008). Alternative splicing and disease. RNA Biol. 5, 17-19.   DOI
19 Kuroyanagi, H., Watanabe, Y., Suzuki, Y., and Hagiwara, M. (2013). Position-dependent and neuron-specific splicing regulation by the CELF family RNA-binding protein UNC-75 in Caenorhabditis elegans. Nucleic Acids Res. 41, 4015-4025.   DOI   ScienceOn
20 Ladd, A.N., Charlet, N., and Cooper, T.A. (2001). The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing. Mol. Cell. Biol. 21, 1285-1296.   DOI   ScienceOn
21 Lim, K.H., Ferraris, L., Filloux, M.E., Raphael, B.J., and Fairbrother, W.G. (2011). Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes. Proc. Natl. Acad. Sci. USA 108, 11093-11098.   DOI   ScienceOn
22 Ren, S., Peng, Z., Mao, J.H., Yu, Y., Yin, C., Gao, X., Cui, Z., Zhang, J., Yi, K., Xu, W., et al. (2012). RNA-seq analysis of prostate cancer in the Chinese population identifies recurrent gene fusions, cancer-associated long noncoding RNAs and aberrant alternative splicings. Cell Res. 22, 806-821.   DOI
23 Marcel, V., Tran, P.L., Sagne, C., Martel-Planche, G., Vaslin, L., Teulade-Fichou, M.P., Hall, J., Mergny, J.L., Hainaut, P., and Van Dyck, E. (2011). G-quadruplex structures in TP53 intron 3:role in alternative splicing and in production of p53 mRNA isoforms. Carcinogenesis 32, 271-278.   DOI   ScienceOn
24 Park, J.Y., Li, W., Zheng, D., Zhai, P., Zhao, Y., Matsuda, T., Vatner, S.F., Sadoshima, J., and Tian, B. (2011). Comparative analysis of mRNA isoform expression in cardiac hypertrophy and deve lopment reveals multiple post-transcriptional regulatory modules. PLoS One 6, e22391.   DOI   ScienceOn
25 Song, H.K., Hong, S.E., Kim, T., and Kim, D.H. (2012). Deep RNA sequencing reveals novel cardiac transcriptomic signatures for physiological and pathological hypertrophy. PLoS One 7, e35552.   DOI   ScienceOn
26 Taft, R.J., Pheasant, M., and Mattick, J.S. (2007). The relationship between non-protein-coding DNA and eukaryotic complexity. Bioessays 29, 288-299.   DOI   ScienceOn
27 Warzecha, C.C., Jiang, P., Amirikian, K., Dittmar, K.A., Lu, H., Shen, S., Guo, W., Xing, Y., and Carstens, R.P. (2010). An ESRPregulated splicing programme is abrogated during the epithelialmesenchymal transition. EMBO J. 29, 3286-3300.   DOI   ScienceOn
28 Taggart, A.J., DeSimone, A.M., Shih, J.S., Filloux, M.E., and Fairbrother, W.G. (2012). Large-scale mapping of branchpoints in human pre-mRNA transcripts in vivo. Nat. Struct. Mol. Biol. 19, 719-721.   DOI   ScienceOn
29 Vencio, R.Z., Brentani, H., Patrao, D.F., and Pereira, C.A. (2004). Bayesian model accounting for within-class biological variability in serial analysis of gene expression (SAGE). BMC Bioinformatics 5, 119.   DOI   ScienceOn
30 Yae, T., Tsuchihashi, K., Ishimoto, T., Motohara, T., Yoshikawa, M., Yoshida, G.J., Wada, T., Masuko, T., Mogushi, K., Tanaka, H., et al. (2012). Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. Nat. Commun. 3, 883.   DOI   ScienceOn
31 Wong, J.J., Ritchie, W., Ebner, O.A., Selbach, M., Wong, J.W., Huang, Y., Gao, D., Pinello, N., Gonzalez, M., Baidya, K., et al. (2013). Orchestrated intron retention regulates normal granulocyte differentiation. Cell 154, 583-595.   DOI   ScienceOn
32 Yamashita, A., Shichino, Y., Tanaka, H., Hiriart, E., Touat-Todeschini, L., Vavasseur, A., Ding, D.Q., Hiraoka, Y., Verdel, A., and Yamamoto, M. (2012). Hexanucleotide motifs mediate recruitment of the RNA elimination machinery to silent meiotic genes. Open Biol. 2, 120014.   DOI
33 Zhou, J., Zheng, X., and Shen, H. (2012). Targeting RNA-splicing for SMA treatment. Mol. Cells 33, 223-228.   DOI
34 Zuo, P., and Manley, J.L. (1993). Functional domains of the human splicing factor ASF/SF2. EMBO J. 12, 4727-4737.
35 Waterston, R.H., Lindblad-Toh, K., Birney, E., Rogers, J., Abril, J.F., Agarwal, P., Agarwala, R., Ainscough, R., Alexandersson, M., An, P., et al. (2002). Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520-562.   DOI   ScienceOn
36 Das, D., Clark, T.A., Schweitzer, A., Yamamoto, M., Marr, H., Arribere, J., Minovitsky, S., Poliakov, A., Dubchak, I., Blume, J.E., et al. (2007). A correlation with exon expression approach to identify cis-regulatory elements for tissue-specific alternative splicing. Nucleic Acids Res. 35, 4845-4857.   DOI   ScienceOn
37 Reinke, L.M., Xu, Y., and Cheng, C. (2012). Snail represses the splicing regulator epithelial splicing regulatory protein 1 to promote epithelial-mesenchymal transition. J. Biol. Chem. 287, 36435-36442.   DOI