Alternative splicing as a regulator of development and tissue identity

Nature Reviews Molecular Cell Biology

Volumn 18, Issue 7, 2017, Pages 437-451

  Baralle, Francisco E ^a   Giudice, Jimena ^b,c  

^a INTERNATIONAL CENTRE FOR GENETIC ENGINEERING AND BIOTECHNOLOGY   (Italy)

^b UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF NORTH CAROLINA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ISOPROTEIN; MESSENGER RNA PRECURSOR; RNA BINDING PROTEIN; RNA SPLICING FACTOR; TRANSCRIPTOME; MESSENGER RNA; PROTEIN;

ALTERNATIVE RNA SPLICING; BRAIN DEVELOPMENT; CELL DIFFERENTIATION; EPIGENETICS; ERYTHROPOIESIS; GERMLINE MICRONUCLEUS; HEART DEVELOPMENT; HEART DISEASE; HUMAN; LIVER DEVELOPMENT; MOLECULAR INTERACTION; MUSCLE DEVELOPMENT; MYOTONIC DYSTROPHY; NERVE CELL DIFFERENTIATION; NEURAL STEM CELL; NEUROLOGIC DISEASE; NONHUMAN; ORGANOGENESIS; PANCREAS; PHYSIOLOGY; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SKELETAL MUSCLE; SMOOTH MUSCLE CELL; STRIATED MUSCLE; T LYMPHOCYTE ACTIVATION; TISSUES; TRANSCRIPTION REGULATION; ANIMAL; GENETICS; METABOLISM;

ALTERNATIVE SPLICING; ANIMALS; HUMANS; PROTEINS; RNA, MESSENGER;

EID: 85019059789     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm.2017.27     Document Type: Review

References (153)

1. Pan, Q., Shai, O., Lee, L. J., Frey, B. J. & Blencowe, B. J. Deep surveying of alternative splicing complexity in the human transcriptome by high-Throughput sequencing. Nat. Genet. 40, 1413-1415 (2008).
2. Wang, E. T. et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470-476 (2008).
3. Kim, M.-S. et al. A draft map of the human proteome. Nature 509, 575-581 (2014).
4. Scotti, M. M. & Swanson, M. S. RNA mis-splicing in disease. Nat. Rev. Genet. 17, 19-32 (2016).
5. Kalsotra, A. et al. A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proc. Natl Acad. Sci. USA 105, 20333-20338 (2008).
6. Bebee, T. W., Cieply, B. W. & Carstens, R. P. Genome-wide activities of RNA binding proteins that regulate cellular changes in the epithelial to mesenchymal transition (EMT). Adv. Exp. Med. Biol. 825, 267-302 (2014).
7. Pradella, D., Naro, C., Sette, C. & Ghigna, C. EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression. Mol. Cancer 16, 8 (2017).
8. Chabot, B. & Shkreta, L. Defective control of pre-messenger RNA splicing in human disease. J. Cell Biol. 212, 13-27 (2016).
9. Singh, R. K. & Cooper, T. A. Pre-mRNA splicing in disease and therapeutics. Trends Mol. Med. 18, 472-482 (2012).
10. Martinez, N. M. et al. Alternative splicing networks regulated by signaling in human T cells. RNA 18, 1029-1040 (2012).
11. Giudice, J. et al. Alternative splicing regulates vesicular trafficking genes in cardiomyocytes during postnatal heart development. Nat. Commun. 5, 3603 (2014).
12. Bhate, A. et al. ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation. Nat. Commun. 6, 8768 (2015).
13. Dillman, A. A. et al. mRNA expression, splicing and editing in the embryonic and adult mouse cerebral cortex. Nat. Neurosci. 16, 499-506 (2013).
14. Singh, R. K. et al. Rbfox2-coordinated alternative splicing of Mef2d and Rock2 controls myoblast fusion during myogenesis. Mol. Cell 55, 592-603 (2014).
15. Llorian, M. et al. The alternative splicing program of differentiated smooth muscle cells involves concerted non-productive splicing of post-Transcriptional regulators. Nucleic Acids Res. 44, 8933-8950 (2016).
16. Fu, X. D. Towards a splicing code. Cell 119, 736-738 (2004).
17. Barash, Y. et al. Deciphering the splicing code. Nature 465, 53-59 (2010).
18. Fu, X.-D. & Ares, M. Context-dependent control of alternative splicing by RNA-binding proteins. Nat. Rev. Genet. 15, 689-701 (2014).
19. Tilgner, H. et al. Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-Transcriptional in the human genome but inefficient for lncRNAs. Genome Res. 22, 1616-1625 (2012).
20. Vargas, D. Y. et al. Single-molecule imaging of transcriptionally coupled and uncoupled splicing. Cell 147, 1054-1065 (2011).
21. Kornblihtt, A. R. et al. Alternative splicing: A pivotal step between eukaryotic transcription and translation. Nat. Rev. Mol. Cell Biol. 14, 153-165 (2013).
22. Perales, R. & Bentley, D. Cotranscriptionality: The transcription elongation complex as a nexus for nuclear transactions. Mol. Cell 36, 178-191 (2009).
23. Neugebauer, K. M. On the importance of being co-Transcriptional. J. Cell Sci. 115, 3865-3871 (2002).
24. Fiszbein, A. et al. Alternative splicing of G9a regulates neuronal differentiation. Cell Rep. 14, 2797-2808 (2016).
25. Luco, R. F., Allo, M., Schor, I. E., Kornblihtt, A. R. & Misteli, T. Epigenetics in alternative pre-mRNA splicing. Cell 144, 16-26 (2011).
26. Ip, J. Y. et al. Global impact of RNA polymerase II elongation inhibition on alternative splicing regulation. Genome Res. 21, 390-401 (2011).
27. Li, Q. et al. The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation. eLife 3, e01201 (2014).
28. Licatalosi, D. D. et al. Ptbp2 represses adult-specific splicing to regulate the generation of neuronal precursors in the embryonic brain. Genes Dev. 26, 1626-1642 (2012).
29. Quesnel-Vallières, M., Irimia, M., Cordes, S. P. & Blencowe, B. J. Essential roles for the splicing regulator nSR100/SRRM4 during nervous system development. Genes Dev. 29, 746-759 (2015).
30. Raj, B. et al. Cross-regulation between an alternative splicing activator and a transcription repressor controls neurogenesis. Mol. Cell 43, 843-850 (2011).
31. Zhang, X. et al. Cell-Type-specific alternative splicing governs cell fate in the developing cerebral cortex. Cell 166, 1147-1162 (2016).
32. Makeyev, E. V., Zhang, J., Carrasco, M. A. & Maniatis, T. The microRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol. Cell 27, 435-448 (2007).
33. Boutz, P. L. et al. A post-Transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. Genes Dev. 21, 1636-1652 (2007).
34. Spellman, R., Llorian, M. & Smith, C. W. J. Crossregulation and functional redundancy between the splicing regulator PTB and its paralogs nPTB and ROD1. Mol. Cell 27, 420-434 (2007).
35. Raj, B. et al. A global regulatory mechanism for activating an exon network required for neurogenesis. Mol. Cell 56, 90-103 (2014).
36. Fogel, B. L. et al. RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. Hum. Mol. Genet. 21, 4171-4186 (2012).
37. Gehman, L. T. et al. The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain. Nat. Genet. 43, 706-711 (2011).
38. Lee, J. A. et al. Cytoplasmic Rbfox1 regulates the expression of synaptic and autism-related genes. Neuron 89, 113-128 (2016).
39. Jensen, K. B. et al. Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability. Neuron 25, 359-371 (2000).
40. Yano, M., Hayakawa-Yano, Y., Mele, A. & Darnell, R. B. Nova2 regulates neuronal migration through an RNA switch in Disabled-1 signaling. Neuron 66, 848-858 (2010).
41. Giampietro, C. et al. The alternative splicing factor Nova2 regulates vascular development and lumen formation. Nat. Commun. 6, 8479 (2015).
42. Forster, E. et al. Emerging topics in Reelin function. Eur. J. Neurosci. 31, 1511-1518 (2010).
43. Beffert, U. et al. Reelin-mediated signaling locally regulates protein kinase B/Akt and glycogen synthase kinase 3beta. J. Biol. Chem. 277, 49958-49964 (2002).
44. Kim, K., Nam, J., Mukouyama, Y. & Kawamoto, S. Rbfox3-regulated alternative splicing of Numb promotes neuronal differentiation during development. J. Cell Biol. 200, 443-458 (2013).
45. Traunmuller, L., Gomez, A. M., Nguyen, T.-M. & Scheiffele, P. Control of neuronal synapse specification by a highly dedicated alternative splicing program. Science 352, 982-986 (2016).
46. Iijima, T. et al. SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1. Cell 147, 1601-1614 (2011).
47. Zibetti, C. et al. Alternative splicing of the histone demethylase LSD1/KDM1 contributes to the modulation of neurite morphogenesis in the mammalian nervous system. J. Neurosci. 30, 2521-2532 (2010).
48. Mauger, O. et al. Alternative splicing regulates the expression of G9A and SUV39H2 methyltransferases, and dramatically changes SUV39H2 functions. Nucleic Acids Res. 43, 1869-1882 (2015).
49. Laurent, B. et al. A specific LSD1/KDM1A isoform regulates neuronal differentiation through H3K9 demethylation. Mol. Cell 57, 957-970 (2015).
50. Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315-322 (2009).
51. Hodges, E. et al. High definition profiling of mammalian DNA methylation by array capture and single molecule bisulfite sequencing. Genome Res. 19, 1593-1605 (2009).
52. Choi, J. K. Contrasting chromatin organization of CpG islands and exons in the human genome. Genome Biol. 11, R70 (2010).
53. Oberdoerffer, S. A conserved role for intragenic DNA methylation in alternative pre-mRNA splicing. Transcription 3, 106-109 (2012).
54. Amit, M. et al. Differential GC content between exons and introns establishes distinct strategies of splice-site recognition. Cell Rep. 1, 543-556 (2012).
55. Gelfman, S., Cohen, N., Yearim, A. & Ast, G. DNA-methylation effect on cotranscriptional splicing is dependent on GC architecture of the exon-intron structure. Genome Res. 23, 789-799 (2013).
56. Gelfman, S. et al. Changes in exon-intron structure during vertebrate evolution affect the splicing pattern of exons. Genome Res. 22, 35-50 (2012).
57. Kucharski, R., Maleszka, J., Foret, S. & Maleszka, R. Nutritional control of reproductive status in honeybees via DNA methylation. Science 319, 1827-1830 (2008).
58. Lyko, F. et al. The honey bee epigenomes: differential methylation of brain DNA in queens and workers. PLoS Biol. 8, e1000506 (2010).
59. Foret, S., Kucharski, R. & Pellegrini, M. DNA methylation dynamics, metabolic fluxes, gene splicing, and alternative phenotypes in honey bees. Proc. Natl Acad. Sci. USA 109, 4968-4973 (2012).
60. Shukla, S. et al. CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing. Nature 479, 74-79 (2011).
61. Phillips, J. E. & Corces, V. G. CTCF: master weaver of the genome. Cell 137, 1194-1211 (2009).
62. Sun, S. et al. ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. Nat. Commun. 6, 6171 (2015).
63. Bentmann, E., Haass, C. & Dormann, D. Stress granules in neurodegeneration-lessons learnt from TAR DNA binding protein of 43 kDa and fused in sarcoma. FEBS J. 280, 4348-4370 (2013).
64. Tollervey, J. R. et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat. Neurosci. 14, 452-458 (2011).
65. Janssens, J. & Van Broeckhoven, C. Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD-ALS spectrum disorders. Hum. Mol. Genet. 22, R77-R87 (2013).
66. Scotter, E. L., Chen, H. J. & Shaw, C. E. TDP-43 proteinopathy and ALS: insights into disease mechanisms and therapeutic targets. Neurotherapeutics 12, 352-363 (2015).
67. Ling, J. P. et al. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science 349, 650-655 (2015).
68. Coady, T. H. & Manley, J. L. ALS mutations in TLS /FUS disrupt target gene expression. Genes Dev. 29, 1696-1706 (2015).
69. Avendaño-Vázquez, S. E. et al. Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection. Genes Dev. 26, 1679-1684 (2012).
70. De Conti, L. et al. TDP-43 affects splicing profiles and isoform production of genes involved in the apoptotic and mitotic cellular pathways. Nucleic Acids Res. 43, 8990-9005 (2015).
71. Weyn-Vanhentenryck, S. M. et al. HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism. Cell Rep. 6, 1139-1152 (2014).
72. Bill, B. R., Lowe, J. K., DyBuncio, C. T. & Fogel, B. L. Orchestration of neurodevelopmental programs by RBFOX1: implications for autism spectrum disorder. Int. Rev. Neurobiol. 113, 251-267 (2013).
73. Voineagu, I. et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380-384 (2011).
74. Irimia, M. et al. A highly conserved program of neuronal microexons is misregulated in autistic brains. Cell 159, 1511-1523 (2014).
75. Lacovich, V. et al. Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons. J. Neurosci. 37, 58-69 (2017).
76. Vuong, C. K., Black, D. L. & Zheng, S. The neurogenetics of alternative splicing. Nat. Rev. Neurosci. 17, 265-281 (2016).
77. Buljan, M. et al. Tissue-specific splicing of disordered segments that embed binding motifs rewires protein interaction networks. Mol. Cell 46, 871-883 (2012).
78. Ellis, J. D. et al. Tissue-specific alternative splicing remodels protein-protein interaction networks. Mol. Cell 46, 884-892 (2012).
79. Giudice, J. & Cooper, T. A. RNA-binding proteins in heart development. Adv. Exp. Med. Biol. 825, 389-429 (2014).
80. Wang, E. T. et al. Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins. Genome Res. 25, 858-871 (2015).
81. Gao, C. et al. RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure. J. Clin. Invest. 126, 195-206 (2016).
82. Gallagher, T. L. et al. Rbfox-regulated alternative splicing is critical for zebrafish cardiac and skeletal muscle functions. Dev. Biol. 359, 251-261 (2011).
83. Salomonis, N. et al. Alternative splicing in the differentiation of human embryonic stem cells into cardiac precursors. PLoS Comput. Biol. 5, e1000553 (2009).
84. Giudice, J., Loehr, J., Rodney, G. G. & Cooper, T. A. Alternative splicing of Snap23, Tmed2, Trip10, and Cltc regulates myofiber structure and skeletal muscle physiology. Cell Rep. 17, 1923-1933 (2016).
85. Labeit, S. & Kolmerer, B. Titins: giant proteins in charge of muscle ultrastructure and elasticity. Science 270, 293-296 (1995).
86. Bang, M. L. et al. The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ. Res. 89, 1065-1072 (2001).
87. Li, S., Guo, W., Dewey, C. N. & Greaser, M. L. Rbm20 regulates titin alternative splicing as a splicing repressor. Nucleic Acids Res. 41, 2659-2672 (2013).
88. Kröger, M. & Linke, W. A. The giant protein titin: A regulatory node that integrates myocyte signaling pathways. J. Biol. Chem. 286, 9905-9912 (2011).
89. Guo, W. et al. RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing. Nat. Med. 18, 766-773 (2012).
90. Refaat, M. M. et al. Genetic variation in the alternative splicing regulator RBM20 is associated with dilated cardiomyopathy. Heart Rhythm 9, 390-396 (2012).
91. Brauch, K. M. et al. Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. J. Am. Coll. Cardiol. 54, 930-941 (2009).
92. Beqqali, A. et al. 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, 452-463 (2016).
93. Haas, J. et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur. Heart J. 36, 1123-1135 (2015).
94. Charton, K. et al. Exploiting the CRISPR/CAS9 system to study alternative splicing in vivo: Application to Titin. Hum. Mol. Genet. 25, 4518-4532 (2016).
95. Beraldi, R. et al. Rbm20-deficient cardiogenesis reveals early disruption of RNA processing and sarcomere remodeling establishing a developmental etiology for dilated cardiomyopathy. Hum. Mol. Genet. 23, 3779-3791 (2014).
96. Maatz, H. et al. RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing. J. Clin. Invest. 124, 3419-3430 (2014).
97. Lara-Pezzi, E., Gómez-Salinero, J., Gatto, A. & García-Pavía, P. The alternative heart: Impact of alternative splicing in heart disease. J. Cardiovasc. Transl Res. 6, 945-955 (2013).
98. Mirtschink, P. et al. HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease. Nature 522, 444-449 (2015).
99. Castle, J. C. et al. Expression of 24, 426 human alternative splicing events and predicted cis regulation in 48 tissues and cell lines. Nat. Genet. 40, 1416-1425 (2008).
100. Runfola, V., Sebastian, S., Dilworth, F. J. & Gabellini, D. Rbfox proteins regulate tissue-specific alternative splicing of Mef2D required for muscle differentiation. J. Cell Sci. 128, 631-637 (2015).
101. Hall, M. P. et al. Quaking and PTB control overlapping splicing regulatory networks during muscle cell differentiation. RNA 19, 627-638 (2013).
102. Sebastian, S. et al. Tissue-specific splicing of a ubiquitously expressed transcription factor is essential for muscle differentiation. Genes Dev. 27, 1247-1259 (2013).
103. Harper, P. Myotonic Dystrophy 3rd edn (W.B. Saunders, 2001).
104. Savkur, R. S., Philips, A. V. & Cooper, T. A. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat. Genet. 29, 40-47 (2001).
105. Savkur, R. S. et al. Insulin receptor splicing alteration in myotonic dystrophy type 2. Am. J. Hum. Genet. 74, 1309-1313 (2004).
106. Fugier, C. et al. Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy. Nat. Med. 17, 720-725 (2011).
107. Kimura, T. et al. Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1. Hum. Mol. Genet. 14, 2189-2200 (2005).
108. Freyermuth, F. et al. Splicing misregulation of SCN5A contributes to cardiac conduction delay and heart arrhythmia in myotonic dystrophy. Nat. Commun. 7, 11067 (2016).
109. Eizirik, D. L. et al. The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genet. 8, e1002552 (2012).
110. Villate, O. et al. Nova1 is a master regulator of alternative splicing in pancreatic beta cells. Nucleic Acids Res. 42, 11818-11830 (2015).
111. Cnop, M. et al. RNA sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate. Diabetes 63, 1978-1993 (2014).
112. Lin, J. C. et al. RBM4 promotes pancreas cell differentiation and insulin expression. Mol. Cell. Biol. 33, 319-327 (2013).
113. Sen, S., Jumaa, H. & Webster, N. J. G. Splicing factor SRSF3 is crucial for hepatocyte differentiation and metabolic function. Nat. Commun. 4, 1336 (2013).
114. Pihlajamäki, J. et al. Expression of the splicing factor gene SFRS10 is reduced in human obesity and contributes to enhanced lipogenesis. Cell Metab. 14, 208-218 (2011).
115. Elizalde, M. et al. Splicing regulator SLU7 is essential for maintaining liver homeostasis. J. Clin. Invest. 124, 2909-2920 (2014).
116. Carreira-Rosario, A. et al. Repression of Pumilio protein expression by Rbfox1 promotes germ cell differentiation. Dev. Cell 36, 562-571 (2016).
117. Slaidina, M. & Lehmann, R. Translational control in germline stem cell development. J. Cell Biol. 207, 13-21 (2014).
118. Soumillon, M. et al. Cellular source and mechanisms of high transcriptome complexity in the mammalian testis. Cell Rep. 3, 2179-2190 (2013).
119. Ramsköld, D., Wang, E. T., Burge, C. B. & Sandberg, R. An abundance of ubiquitously expressed genes revealed by tissue transcriptome sequence data. PLoS Comput. Biol. 5, e1000598 (2009).
120. Schmid, R. et al. The splicing landscape is globally reprogrammed during male meiosis. Nucleic Acids Res. 41, 10170-10184 (2013).
121. Zagore, L. L. et al. RNA binding protein Ptbp2 is essential for male germ cell development. Mol. Cell. Biol. 35, 4030-4042 (2015).
122. Paronetto, M. P. et al. Sam68 marks the transcriptionally active stages of spermatogenesis and modulates alternative splicing in male germ cells. Nucleic Acids Res. 39, 4961-4974 (2011).
123. Luco, R. F. et al. Regulation of alternative splicing by histone modifications. Science 327, 996-1000 (2010).
124. Iwamori, N. et al. MRG15 is required for pre-mRNA splicing and spermatogenesis. Proc. Natl Acad. Sci. USA 113, E5408-E5415 (2016).
125. Gaudreau, M.-C., Heyd, F., Bastien, R., Wilhelm, B. & Möröy, T. Alternative splicing controlled by heterogeneous nuclear ribonucleoprotein L regulates development, proliferation, and migration of thymic pre-T cells. J. Immunol. 188, 5377-5388 (2012).
126. Shankarling, G., Cole, B. S., Mallory, M. J. & Lynch, K. W. Transcriptome-wide RNA interaction profiling reveals physical and functional targets of hnRNP L in human T cells. Mol. Cell. Biol. 34, 71-83 (2014).
127. Yarosh, C. A. et al. TRAP150 interacts with the RNA-binding domain of PSF and antagonizes splicing of numerous PSF-Target genes in T cells. Nucleic Acids Res. 43, 9006-9016 (2015).
128. Ajith, S. et al. Position-dependent activity of CELF2 in the regulation of splicing and implications for signal-responsive regulation in T cells. RNA Biol. 13, 569-581 (2016).
129. Mallory, M. J. et al. Induced transcription and stability of CELF2 mRNA drives widespread alternative splicing during T-cell signaling. Proc. Natl Acad. Sci. USA 112, E2139-E2148 (2015).
130. Ni, T. et al. Global intron retention mediated gene regulation during CD4+ T cell activation. Nucleic Acids Res. 44, 6817-6829 (2016).
131. Martinez, N. M. et al. Widespread JNK-dependent alternative splicing induces a positive feedback loop through CELF2-mediated regulation of MKK7 during T-cell activation. Genes Dev. 29, 2054-2066 (2015).
132. Cole, B. S. et al. Global analysis of physical and functional RNA targets of hnRNP L reveals distinct sequence and epigenetic features of repressed and enhanced exons. RNA 21, 2053-2066 (2015).
133. Rothrock, C., House, A. & Lynch, K. W. HnRNP L represses exon splicing via a regulated exonic splicing silencer. EMBO J. 24, 2792-2802 (2005).
134. Yamamoto, M. L. et al. Alternative pre-mRNA splicing switches modulate gene expression in late erythropoiesis. Blood 113, 3363-3370 (2009).
135. Hou, V. C. et al. Decrease in hnRNP A/B expression during erythropoiesis mediates a pre-mRNA splicing switch. EMBO J. 21, 6195-6204 (2002).
136. Cheng, A. W. et al. Muscleblind-like 1 (Mbnl1) regulates pre-mRNA alternative splicing during terminal erythropoiesis. Blood 124, 598-610 (2014).
137. Pimentel, H. et al. A dynamic alternative splicing program regulates gene expression during terminal erythropoiesis. Nucleic Acids Res. 42, 4031-4042 (2014).
138. Pimentel, H. et al. A dynamic intron retention program enriched in RNA processing genes regulates gene expression during terminal erythropoiesis. Nucleic Acids Res. 44, 838-851 (2016).
139. Yan, Q. et al. Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators. Proc. Natl Acad. Sci. USA 112, 3445-3450 (2015).
140. Charizanis, K. et al. Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy. Neuron 75, 437-450 (2012).
141. Pilaz, L.-J. & Silver, D. L. Post-Transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain. Wiley Interdiscip. Rev. RNA 6, 501-515 (2015).
142. Raj, B. & Blencowe, B. J. Alternative splicing in the mammalian nervous system: recent insights into mechanisms and functional roles. Neuron 87, 14-27 (2015).
143. Blech-Hermoni, Y. & Ladd, A. N. RNA binding proteins in the regulation of heart development. Int. J. Biochem. Cell Biol. 45, 2467-2478 (2013).
144. Van Den Hoogenhof, M. M. G., Pinto, Y. M. & Creemers, E. E. RNA splicing regulation and dysregulation in the heart. Circ. Res. 118, 454-468 (2016).
145. Licatalosi, D. D. Roles of RNA-binding proteins and post-Transcriptional regulation in driving male germ cell development in the mouse. Adv. Exp. Med. Biol. 907, 123-151 (2016).
146. Martinez, N. M. & Lynch, K. W. Control of alternative splicing in immune responses: many regulators, many predictions, much still to learn. Immunol. Rev. 253, 216-236 (2013).
147. Yabas, M., Elliott, H. & Hoyne, G. The role of alternative splicing in the control of immune homeostasis and cellular differentiation. Int. J. Mol. Sci. 17, E3 (2015).
148. Conboy, J. G. RNA splicing during terminal erythropoiesis. Curr. Opin. Hematol. 24, 215-221 (2017).
149. Bland, C. S. et al. Global regulation of alternative splicing during myogenic differentiation. Nucleic Acids Res. 38, 7651-7664 (2010).
150. Wells, Q. S. et al. Whole exome sequencing identifies a causal RBM20 mutation in a large pedigree with familial dilated cardiomyopathy. Circ. Cardiovasc. Genet. 6, 317-326 (2013).
151. Echeverria, G. V. & Cooper, T. A. RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity. Brain Res. 1462, 100-111 (2012).
152. Goodwin, M. et al. MBNL sequestration by toxic RNAs and RNA misprocessing in the myotonic dystrophy brain. Cell Rep. 12, 1159-1168 (2015).
153. Chau, A. & Kalsotra, A. Developmental insights into the pathology of and therapeutic strategies for DM1: back to the basics. Dev. Dyn. 244, 377-390 (2015).