SUPPLEMENTARY INFORMATION

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1 Supplementary Table 1. RNA-binding proteins (RBPs) regulating alternative splicing in developmental or differentiation contexts RBP Context where RBP regulates alternative splicing Binding motif from CLIP-sequencing experiments / alternative splicing effect CELF1 - Heart development Skeletal muscle development 3 UGUU motifs / skipping or inclusion (position dependent) 3,5,6 - Myoblast differentiation (C2C12 cells) 4 CELF2 - T-cell activation Heart development 3 UGU-rich motifs 8 ELAVL - Brain development 10 U- and AU-rich motifs ESRP1 ESRP2 - Liver development (ESRP2) 13 - Epithelial-mesenchymal transition (ESRP1/2) 14 - Stomach smooth muscle development (ESRP1) 15 - Epidermis development (ESRP1/2) 16 - Kidney development (ESRP1/2) 17 GU-rich motifs / skipping or inclusion (position dependent) 18 HNRNPL - T-cell development CA-rich motifs / skipping or inclusion 20,22 HNRNPLL - T-cell activation 23 CA-rich motifs / skipping or inclusion 24 - B-cell into plasma cell differentiation 24 MBNL1 MBNL2 - Heart development (MBNL1) Brain development (MBNL2) 25 - Erythropoiesis (MBNL1) 26 NOVA1 - Brain development (NOVA1/2) 28,29 NOVA2 - Vascular development (endothelial cells) (NOVA2) 30 PTBP1 - Brain development PTBP2 - Male germ cell development (PTBP2) 35 - Myoblast differentiation (C2C12 cells) 36 - Primary smooth muscle cell (aorta, bladder) differentiation (PTBP1) 37 QK - Myoblast differentiation (C2C12 cells) 36 - Vascular smooth muscle development and cell dedifferentiation 37,39 RBFOX1 RBFOX2 - Brain development 34, Heart development 45,46 - Skeletal muscle development 46,47 - Myoblast differentiation (C2C12 cells) 48,49 RBM4 - Pancreas development and pancreatic cell differentiation (AR42J cells) 52 - Neuronal differentiation (P19 cells) 53 YGCY (preferred: UGCU) / skipping or inclusion (position dependent) 25,27 YCAY motifs / skipping or inclusion (position dependent) 31 CU-rich motif / skipping 33,38 RBM20 - Heart development 56 UCUU / skipping 56 RBM24 - Heart and skeletal muscle development 57 G(A/U)GUG 58 SAM68 - Spermatogenesis 59 - T-cell activation 60 - Brain development 61,62 - Adipogenesis 63 UAA-rich motifs / skipping or inclusion (position dependent) 40 UGCAUG / inclusion (downstream binding) or skipping (upstream binding or within alternative exon) 50,51 CGG or GTAACG / skipping or inclusion (position dependent) 54,55 AU-rich motifs SRRM4 - Brain development and synaptogenesis 64,65 UGC-rich motifs between polypyrimidine tract and 3 ss / inclusion 66 SRSF1 - Heart development 67 GGAGGA / inclusion 68 SRSF10 - Heart development 69,70 - Skeletal muscle development, myoblast differentiation (C2C12 cells) 70 - Adipogenic differentiation 71 GA-rich motifs / skipping or inclusion (position dependent) 69,72

2 Supplementary references 1. Kalsotra, A. et al. A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proc. Natl. Acad. Sci. U. S. A. 105, (2008). 2. Giudice, J. et al. Alternative splicing regulates vesicular trafficking genes in cardiomyocytes during postnatal heart development. Nat. Commun. 5, 3603 (2014). 3. Wang, E. T. et al. Antagonistic regulation of mrna expression and splicing by CELF and MBNL proteins. Genome Res. 25, (2015). 4. Bland, C. S. et al. Global regulation of alternative splicing during myogenic differentiation. Nucleic Acids Res. 38, (2010). 5. Daughters, R. S. et al. RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genet. 5, (2009). 6. Masuda, A. et al. CUGBP1 and MBNL1 preferentially bind to 3 UTRs and facilitate mrna decay. Sci. Rep. 2, 209 (2012). 7. Martinez, N. M. et al. Alternative splicing networks regulated by signaling in human T cells. RNA 18, (2012). 8. 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, (2016). 9. Mallory, M. J. et al. Induced transcription and stability of CELF2 mrna drives widespread alternative splicing during T-cell signaling. Proc. Natl. Acad. Sci. U. S. A. 112, E (2015). 10. Ince-Dunn, G. et al. Neuronal Elav-like (Hu) proteins regulate RNA splicing and abundance to control glutamate levels and neuronal excitability. Neuron 75, (2012). 11. Lebedeva, S. et al. Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR. Mol. Cell 43, (2011). 12. Mukherjee, N. et al. Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mrna processing and mrna stability. Mol. Cell 43, (2011). 13. Bhate, A. et al. ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation. Nat. Commun. 6, 8768 (2015). 14. Warzecha, C. C. et al. An ESRP-regulated splicing programme is abrogated during the epithelialmesenchymal transition. EMBO J. 29, (2010). 15. Sagnol, S., Marchal, S., Yang, Y., Allemand, F. & de Santa Barbara, P. Epithelial splicing regulatory protein 1 (ESRP1) is a new regulator of stomach smooth muscle development and

3 plasticity. Dev. Biol. 414, (2016). 16. Bebee, T. W. et al. The splicing regulators Esrp1 and Esrp2 direct an epithelial splicing program essential for mammalian development. Elife 4, (2015). 17. Bebee, T. W. et al. Ablation of the epithelial specific splicing factor Esrp1 results in ureteric branching defects and reduced nephron number. Dev. Dyn. 245, (2016). 18. Dittmar, K. a. et al. Genome-wide determination of a broad ESRP-regulated posttranscriptional network by high-throughput sequencing. Mol. Cell. Biol. 32, (2012). 19. 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, (2015). 20. 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, (2014). 21. 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, (2012). 22. Rossbach, O. et al. Crosslinking-immunoprecipitation (iclip) analysis reveals global regulatory roles of hnrnp L. RNA Biol. 11, (2014). 23. Cho, V. et al. The RNA-binding protein hnrnpll induces a T cell alternative splicing program delineated by differential intron retention in polyadenylated RNA. Genome Biol. 15, R26 (2014). 24. Chang, X., Li, B. & Rao, A. RNA-binding protein hnrnpll regulates mrna splicing and stability during B-cell to plasma-cell differentiation. Proc. Natl. Acad. Sci. U. S. A. 112, E (2015). 25. Charizanis, K. et al. Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation in Myotonic Dystrophy. Neuron 75, (2012). 26. Cheng, A. W. et al. Muscleblind-like 1 (Mbnl1) regulates pre-mrna alternative splicing during terminal erythropoiesis. Blood 124, (2014). 27. Wang, E. T. et al. Transcriptome-wide regulation of pre-mrna splicing and mrna localization by muscleblind proteins. Cell 150, (2012). 28. Jensen, K. B. et al. Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability. Neuron 25, (2000). 29. Yano, M., Hayakawa-Yano, Y., Mele, A. & Darnell, R. B. Nova2 regulates neuronal migration through an RNA switch in Disabled-1 signaling. Neuron 66, (2010).

4 30. Giampietro, C. et al. The alternative splicing factor Nova2 regulates vascular development and lumen formation. Nat. Commun. 6, 8479 (2015). 31. Licatalosi, D. D. et al. HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456, (2008). 32. Li, Q. et al. The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation. Elife 3, e01201 (2014). 33. Licatalosi, D. D. et al. Ptbp2 represses adult-specific splicing to regulate the generation of neuronal precursors in the embryonic brain. Genes Dev. 26, (2012). 34. Zhang, X. et al. Cell-type-specific alternative splicing governs cell fate in the developing cerebral cortex. Cell 166, (2016). 35. Zagore, L. L. et al. RNA binding protein Ptbp2 is essential for male germ cell development. Mol. Cell. Biol. 35, (2015). 36. Hall, M. P. et al. Quaking and PTB control overlapping splicing regulatory networks during muscle cell differentiation. RNA 19, (2013). 37. 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, (2016). 38. Xue, Y. et al. Genome-wide Analysis of PTB-RNA interactions reveals a strategy used by the general splicing repressor to modulate exon inclusion or skipping. Mol. Cell 36, (2009). 39. Van Der Veer, E. P. et al. Quaking, an RNA-binding protein, is a critical regulator of vascular smooth muscle cell phenotype. Circ. Res. 113, (2013). 40. Hafner, M. et al. Transcriptome-wide identification of RNA-binding protein and microrna target sites by PAR-CLIP. Cell 141, (2010). 41. Gehman, L. T. et al. The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain. Nat. Genet. 43, (2011). 42. Gehman, L. T. et al. The splicing regulator Rbfox2 is required for both cerebellar development and mature motor function. Genes Dev. 26, (2012). 43. 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, (2013). 44. Fogel, B. L. et al. RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. Hum Mol Genet 21, (2012).

5 45. Gao, C. et al. RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure. J. Clin. Invest. 126, (2016). 46. Gallagher, T. L. et al. Rbfox-regulated alternative splicing is critical for zebrafish cardiac and skeletal muscle functions. Dev. Biol. 359, (2011). 47. Pedrotti, S. et al. The RNA-binding protein Rbfox1 regulates splicing required for skeletal muscle structure and function. Hum. Mol. Genet. 24, (2015). 48. Singh, R. K. et al. Rbfox2-coordinated alternative splicing of Mef2d and Rock2 controls myoblast fusion during myogenesis. Mol. Cell 55, (2014). 49. 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, (2015). 50. Yeo, G. W. et al. An RNA code for the FOX2 splicing regulator revealed by mapping RNA-protein interactions in stem cells. Nat. Struct. Mol. Biol. 16, (2009). 51. Weyn-Vanhentenryck, S. M. et al. HITS-CLIP and integrative modeling define the Rbfox splicingregulatory network linked to brain development and autism. Cell Rep. 6, (2014). 52. Lin, J. C. et al. RBM4 promotes pancreas cell differentiation and insulin expression. Mol Cell Biol 33, (2013). 53. Tarn, W.-Y. et al. RBM4 promotes neuronal differentiation and neurite outgrowth via modulating Numb isoform expression. Mol. Biol. Cell 4, 1 16 (2016). 54. Wang, Y., Ma, M., Xiao, X. & Wang, Z. Intronic splicing enhancers, cognate splicing factors and context-dependent regulation rules. Nat. Struct. Mol. Biol. 19, (2012). 55. Uniacke, J. et al. An oxygen-regulated switch in the protein synthesis machinery. Nature 486, (2012). 56. Maatz, H. et al. RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mrna processing. J. Clin. Invest. 124, (2014). 57. Yang, J. et al. RBM24 Is a major regulator of muscle-specific alternative splicing. Dev. Cell 31, (2014). 58. Ray, D. et al. A compendium of RNA-binding motifs for decoding gene regulation. Nature 499, (2013). 59. 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, (2011). 60. Matter, N., Herrlich, P. & König, H. Signal-dependent regulation of splicing via phosphorylation of

6 Sam68. Nature 420, (2002). 61. Lukong, K. E. & Richard, S. Motor coordination defects in mice deficient for the Sam68 RNAbinding protein. Behav. Brain Res. 189, (2008). 62. Iijima, T. et al. SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1. Cell 147, (2011). 63. Huot, M. E. et al. The Sam68 STAR RNA-binding protein regulates mtor alternative splicing during adipogenesis. Mol. Cell 46, (2012). 64. Raj, B. et al. Cross-regulation between an alternative splicing activator and a transcription repressor controls neurogenesis. Mol. Cell 43, (2011). 65. 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, (2015). 66. Raj, B. et al. A global regulatory mechanism for activating an exon network required for neurogenesis. Mol. Cell 56, (2014). 67. Xu, X. et al. ASF/SF2-regulated CaMKII delta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle. Cell 120, (2005). 68. Sanford, J. R. et al. Splicing factor SFRS1 recognizes a functionally diverse landscape of RNA transcripts. Genome Res. 19, (2009). 69. Feng, Y. et al. SRp38 regulates alternative splicing and is required for Ca2+ handling in the embryonic heart. Dev. Cell 16, (2009). 70. Wei, N. et al. SRSF10 plays a role in myoblast differentiation and glucose production via regulation of alternative splicing. Cell Rep. 13, (2015). 71. Li, H. et al. SRSF10 regulates alternative splicing and is required for adipocyte differentiation. Mol. Cell. Biol. 34, (2014). 72. Zhou, X. et al. Transcriptome analysis of alternative splicing events regulated by SRSF10 reveals position-dependent splicing modulation. Nucleic Acids Res. 42, (2014).

Mechanisms of alternative splicing regulation

Mechanisms of alternative splicing regulation The number of mechanisms that are known to be involved in splicing regulation approximates the number of splicing decisions that have been analyzed in detail.