Table 2.
Known auxiliary intronic elements that regulate alternative splicing
| Exon or intron that is regulated | Type of splice site choice | Specificity of splicing* | Type of element (name) | Sequence† | Location of element (nucleotide number relative to alternative exon) | Associated trans factor(s) | Reference |
| 4.1R exon 16 (human) | Cassette | Developmental stage-specific | Enhancer | AUUUAUUuuuAAAUAUuuuUUGGUUUGCCAAUUUUCAGUuuuUCCCG | Upstream (-106 to -59) | Unknown | [53] |
| 4.1R exon 16 (human) | Cassette | Developmental stage-specific | Enhancer | UGUAUgaAcUUGAagcUUAUUUCAgUuGgUUGCCUGgAacCUUCUGCAUUcuUugCUGAUCCCCUUUUCUUCAUUCUgUgcugCAUUUGGUUUugCaUGCAAUUgCauGAAGGGACUUuAGgUuUAAAAUGCuUuUGcAUGUU | Downstream (+4 to 146) | Unknown | [53] |
| α-actinin NM/SM exons (rat) | Mutually exclusive exons | Smooth muscle-specific | Silencer | Not defined | Upstream of SM exon | PTB‡ | [54] |
| α-actinin NM/SM exons (rat) | Mutually exclusive exons | Smooth muscle-specific | Enhancer (BP-URE) | CCUUGUCUGUGUGUCUAACUGUGUGCAC | Upstream of NM exon | ETR-3‡, Brul‡ | [55] |
| Agrin Y exon (exon 28, mouse) | Cassette | Neuron-specific | Enhancer | uuaccCAACUcaacucaCC | Downstream (+15 to 33) | Unknown | [56] |
| Agrin Y exon (exon 28, mouse) | Cassette | Neuron-specific | Enhancer | aucuuuuguAGCCAUUCCuagagAGCccuuuccc | Downstream (+34 to 68) | Unknown | [56] |
| AMP deaminase 1 exon 2 (human) | Cassette | Developmental Stage-specific | Enhancer (ExRE) | GCCCAGGCUGGAGUGCAGUA | Downstream (about +1.7 kb) | Unknown | [57] |
| AMP deaminase 1 exon 2 (human) | Cassette | Developmental stage-specific | Enhancer (ExRE) | CCAUCGAAUGCAUUUACUU | Downstream (about +3 kb) | Unknown | [57] |
| Amyloid precursor protein exon 8 (human) | Cassette | Neuron-specific | Enhancer | AUGUUU | Upstream (-47 to -42) | Unknown | [58] |
| Amyloid precursor protein exon 8 (human) | Cassette | Neuron-specific | Silencer | UUU | Upstream (-38 to -36) | Unknown | [58] |
| Calcitonin/CGRP exon 4 (human) | Cassette (contains alternative poly(A) site) | Cell type-specific | Enhancer (rep1) | CCAAGGGAAAgcaugGGUUAACCUA | Upstream (-254 to -230) | Unknown | [59] |
| Calcitonin/CGRP exon 4 (human) | Cassette (contains alternative poly(A) site) | Cell type-specific | Enhancer (rep2) | CAGCCCUGGugcaugGCACUGCCUC | Upstream (-34 to -10) | Unknown | [59] |
| Calcitonin/ CGRP exon 4 (human) | Cassette (contains alternative poly-A site) | Cell type-specific | Enhancer | CUCCGCUCCUCUUCcagguaagac | Downstream (+204 to 238) | PTB‡, ASF/SF2‡ U1 snRNP, SRp20‡ | , [60,61,62] |
| Cardiac troponin T exon 5 (chicken) | Cassette | Embryonic, muscle-specific | Silencer (MSE1) | CCUCUGCGCUUCUUCCCUUCCCUCCUCCCUGGCUCA | Upstream (-36 to -1) | PTB‡, U2AF65 | [17,63] |
| Cardiac troponin T exon 5 (chicken) | Cassette | Embryonic, muscle-specific | Enhancer, Silencer (MSE2) | ACUGCACCUUUCUUUGUUCCAUCUCUCCACCUCUGCUGUG | Downstream (+7 to +46) | PTB‡, ETR-3‡ | [17,64] |
| Cardiac troponin T exon 5 (chicken) | Cassette | Embryonic, muscle-specific | Enhancer (MSE3) | UCGCGGGUCGGUGUGUCCUGUGCCUUUCCCUGCUU | Downstream (+53 to 87) | ETR-3‡, PurH‡ | [17,64,65] |
| Cardiac troponin T exon 5 (chicken) | Cassette | Embryonic muscle-specific | Silencer (MSE4) | CGCUUUCCUUUCAU UCUUUCACUUCUCUGCUGCUUUU | Downstream (+81 to 117) | PTB‡ | [17,64] |
| Caspase-2 exon 9 (mouse) | Cassette | Brain and skeletal muscle-specific; associated with apoptosis | Silencer (In50 up) | GCUuauuaacUGCAAUGUAcuuuuuauuguuuuucauuccaGUUAAGG | Downstream (+141 to 188) | U2 snRNP | [66,67] |
| Caspase-2 exon 9 (mouse) | Cassette | Brain and skeletal muscle-specific; associated with apoptosis | Silencer (In50dn) | AUUUCUGCUUGACUCUUCCAAAUCUUCCUUCUCUUACCCUUGCAUUUUCUCUCUGU | Downstream (+189 to 244) | PTB‡ | [66,67] |
| Chloride channel ClC-1 intron 2 (human) | Intron retention | Aberrant inclusion in myotonic dystrophy | Enhancer | UCUUGGGUAUAGCACCCAAAGUAAAGUAGUGACUCGUUAGCUGCUUUUCUCUCUCUCUCUCUCUCUCUCUCUCUCUCUCUGUCUCUACAUAUAUAUAUUUUUGUUUGUUUGUUUGUUUGUUGUUUGUUUGUUUGUUUUUUCCCUCAUCUC UUCCUAG | Upstream of exon 3 (-156 to -1) | CUG-BP‡ | [2] |
| Clathrin light chain B exon EN (rat) | Cassette | Neuron-specific | Silencer | CUCUUUCUCUUUAACCCUGUGCCUGCCUGUCUUGCUGUCUGUCUUCCCCCACCUAACUCCUUCUCCUAACGGUUUUCCUCAAG | Upstream (-85 to -1) | PTB‡, CUG-BP | [68] |
| c-src N1 exon (mouse) | Cassette | Neuron-specific | Silencer | GGGCCCUGUCUUCGCACCUCAGCCUCUCCUUCUCUCUGCUUCUCUCUCGCUGGCCCUU | Upstream (-60 to -3) | PTB‡/nPTB | [69] |
| c-src N1 exon (mouse) | Cassette | Neuron-specific | Enhancer, silencer (DCS) | UGAGGCUGGGGGCUGCUCUCUGCAUGUGCUUCCU | Downstream (+37 to 70) | PTB‡/nPTB, KSRP‡, FBP‡, hnRNP H‡, hnRNP F‡ | [69,70,71] |
| Cystic fibrosis transmembrane regulator exon 9 (human) | Cassette | Aberrantly skipped in cystic fibrosis | Silencer (ISS) | Not published | Downstream (+117 to 264) | SR proteins | [72] |
| Dopa decarboxylase exon B (Drosophila) | Cassette | Tissue-specific | Silencer | Not published | Upstream (+84 to 528) | Unknown | [73] |
| DMPK exon 16 (human) | Alternative terminal exon | Developmental stage-specific; skipped in DM | Enhancer | (CUG)n | Upstream (about 35 nucleotides) | Unknown | [74] |
| Fibroblast growth factor receptor 1 α exon (human) | Cassette | Skipped in glial cell tumors | Silencer (ISS-1) | AAugcugcUACAGCUGC UUCCUAACUUUGCCUCUUUCUUC | Upstream (-242 to -281) | PTB* | [75,76] |
| Fibroblast growth factor receptor 1 α exon (human) | Cassette | Skipped in glial cell tumors | Silencer (ISS-2) | AUCUGCCCCCACUCUGCUUCAGAAACugcugcCCACUAACAUUGCUCCCugccugcCGCGUG | Downstream (+98 to 159) | Unknown | [77] |
| Fibroblast growth factor receptor 2 BEK/K-SAM (IIIb/IIIc) exons (human) | Mutually exclusive exons | Cell-type specific | Enhancer (IAS1) | CUUUCAUUUUUGUCUUUUUUU | Downstream of K-SAM (+10 to 29) | TIA-1‡ | [78,79] |
| Fibroblast growth factor receptor 2 BEK/K-SAM (IIIb/IIIc) exons (human) | Mutually exclusive exons | Cell-type specific | Enhancer (IAS2) | CCAUGGAAAAAUGCC CACAAC | Downstream of K-SAM (+168 to 188) | Unknown | [80] |
| Fibroblast growth factor receptor 2 BEK/K-SAM (IIIb/IIIc) exons (human) | Mutually exclusive exons | Cell-type specific | Enhancer (IAS3) | UGUGGGUUGAUUUUUUCCAUGCGUUUGAUUGCGUGCAUGUGUAGGAGGUGAAGCCGGUGU | Downstream of K-SAM (+963 to 1021) | Unknown | [80] |
| Fibroblast growth factor receptor 2 IIIb/IIIc exons (rat) | Mutually exclusive exons | Cell-type specific | Enhancer (IIIb), silencer (IIIc) (ISAR) | CAAACAAAUUCAAAGAGAACGGACUCUGUgggcugauuuuuccauguGUUCAAUCGC | Downstream of IIIb (+915 to 978) | Unknown | [81] |
| Fibroblast growth factor receptor 2 IIIb/IIIc exons (rat) | Mutually exclusive exons | Cell-type specific | Silencer (ISS1) | CUCAUUGUGAUCUCCUCCCUCCCACAGCUCUUUAGGUGUA | Upstream of IIIb (-143 to -112) | PTB‡ | [82] |
| Fibroblast growth factor receptor 2 IIIb/IIIc exons (rat) | Mutually exclusive exons | Cell-type specific | Silencer (ISS2) | UGGUGGGACCAUAGGCAGCAC | Upstream of IIIb | Unknown | [82] |
| Fibronectin exon EIIIB (rat) | Cassette | Cell-type specific | Enhancer (ICR) | UCUUAAAGGUUCUCUGCCCugcaugGGAAGAAACAUUGCUGAGAACCACUGugcaugAACCCCCUCACUUGUGAUACGAGUUCACUGAAUGACAUUACGGCAAUGCAGUAGUGUGUAGAUAC | Downstream (+519 to 640) | Unknown | [83,84] |
| GABAA receptor subunit γ2 24 nucleotide exon (rat) | Cassette | Neuron-specific | Silencer (rs1) | UGUUUCUCUUUCUCUCCUUU | Upstream (-89 to -70) | PTB‡ | [85] |
| GABAA receptor subunit γ2 24 nucleotide exon (rat) | Cassette | Neuron-specific | Silencer (rs2) | CCUUUUCCUUCUUCUUAUU | Upstream (-69 to -51) | PTB‡ | [85] |
| GABAA receptor subunit γ2 24 nucleotide exon (rat) | Cassette | Neuron-specific | Silencer (rs3) | GCAAUUCUCUUUUCUGUCU | Upstream (-31 to -13) | PTB‡ | [85] |
| GABAA receptor subunit γ2 24 nucleotide exon (rat) | Cassette | Neuron-specific | Enhancer | ACAAAUCCA | Upstream (-12 to -4) | Unknown | [85,86] |
| gag gene (Rous sarcoma virus) | Spliced versus unspliced | Infection stage-specific | Silencer (NRS) | CCGGAGUGCUCGAGAAACCAGCAACGGAGCGGCGAAUCGACAAAGGGGAGGAAGUGGGAGAAACAACUGUGCAGCGAGAUGCGAAGAUGGCGCCGGAGGAAACGGCCACACCUAAAACCGUUGGCACAUCCUGCUAUCAUUGCGGAACAGCUAUUGGCUGUAAUUGCGccacagccucggcucccuccuccuccuuauguggggagugguuuguauccuucccu | Downstream of 5 splice site (about 300 nucleotides) | hnRNP H‡, SF2/ASF‡ | [87,88,89] |
| Glycine receptor α2 exon 3A (human) | Cassette | Neuron-specific | Enhancer | UCAUCAUCAUUUCAU | Upstream (about 80 nucleotides) | Nova-1‡ | [31,90] |
| hnRNP A1 exon 7B (mouse) | Cassette | Auto-regulated | Enhancer (CE1) | UAAGGAGUCUGUAAGUAAUGGUUUCUGGAAAACCUGUACCUUUAGAGUAGGCUAGUAGAAACUAAACUUAGUGCAUGACAAAGUUCGAUCAGUCCCAUAAAUGUGCAUG | Upstream (-194 to -86) | hnRNP A1‡ | [21] |
| hnRNP A1 exon 7B (mouse) | Cassette | Auto-regulated | Enhancer (CE4) | AGCUAGAUUAGACUU CUAGAGUUU | Downstream (+35 to 58) | hnRNP A1‡ | [21,91] |
| hnRNP A1 exon 7B (mouse) | Cassette | Auto-regulated | Silencer (CE6IO) | CCUGCUCUGCUGUGCUACCUCCUCCUGGCUUUAAGCUGGGGCCGCCUCCCCAAAAUAAGUAGGUGAAUGAGUGGUUA | Downstream (+128 to 204) | Unknown | [11] |
| hnRNP A1 exon 7B (mouse) | Cassette | Auto-regulated | Silencer (CE9) | CUGGAUUAUUAACUGAAUGCCUCACUCAGAGAAUGAA | Downstream (+372 to 418) | Unknown | [92] |
| Major late region 1 (L1) 52,55K/IIIa (adenovirus) | Alternative 3' splice sites | Infection stage-specific | Silencer | GCGUGGAGGAAUAUGACGAGGACGAUGAGUACGAGCCAGAGGACGGCGA | Upstream of IIIa splice site (-76 to -28) | SR proteins | [93] |
| Major late region 1 (L1) 52,55K/IIIa (adenovirus) | Alternative 3' splice sites | Infection stage-specific | Enhancer | AGUACUAAGCggugauguuucugaucag | Upstream of IIIa splice site (-28 to -1) | Unknown | [94] |
| MVM NS2-specific exon and small intron (parvovirus) | Cassette, alternative 5' and 3' splice sites | Infection stage-specific | Enhancer (IES) | GUUUAAGggAUgGUUgGUUgGUGgggU | Downstream of NS2 exon, small intron D2 5 splice site | Unknown | [95] |
| Myosin heavy chain exon 11e (Drosophila) | Mutually exclusive exons 11a-e | Muscle type-specific | Silencer (CIE1) | AUGUACCAUGUACC | Downstream of exon 11e | Unknown | [96] |
| Myosin heavy chain exon 11e (Drosophila) | Mutually exclusive exons 11a-e | Muscle type-specific | Enhancer (CIE2) | AGUGCUGUGU | Downstream of exon 11e | Unknown | [96] |
| Myosin heavy chain exon 11e (Drosophila) | Mutually exclusive exons 11a-e | Muscle type-specific | Enhancer (CIE3) | AUCCAUCCCUCUAUCUAUCCCAGUUCAACCUGUCCAAAAGUGUUUUUGAAGAACCGCUUAAGCAUAAGCAAAAAAA | Upstream of exon 12 (about -200 nucleotides) | Unknown | [96] |
| NCAM MSDb exon (mouse) | Cassette | Muscle-specific, developmental stage-specific | Silencer (DSRE) | GACCUCACUGACCCAGCUGGGCCUUUGUCACAUUGGGGGAGCCUGGUUCUUUUCCUCUCAUUCUCUUAACUGUCUAUACUUUAGUUCUUUGAAUCUGGAGGAGUGGAACAGGUCCACUCUUUGGAAACUUGAACCUGGCUUUCUAGU | Downstream (+626 to 771) | Unknown | [97] |
| NMDA exon 5 (rat) | Cassette | Neuron-specific | Silencer | GCUUUAGCGCCGUCAUUUUCAACCGUUUAUAAUCUUCUUCUGUGUCUGCAUAUUUUCUCUGUGCACAUUAUUCAUCAG | Upstream (-78 to -1) | PTB‡, CUG-BP | [68] |
| Non-muscle myosin II heavy chain B exon N30 (human) | Cassette | Neuron-specific | Enhancer (IDDE) | GAUUugcaugucguacugcauguGUCCACUGUGCACACAAUC | Downstream (+1.5 kb) | Unknown | [98] |
| Nova-1 exon H (mouse) | Cassette | Neuron-specific | Enhancer | GCCAAUCAGGUACAGUAUCAUCCUCUCAUCCUACACCAUACUUUCACAGCGGUUG | Downstream (+8 to 62) | Nova-1‡ | [31] |
| sex lethal exon 3 (Drosophila) | Cassette | Male-specific | Silencer | UUUUUUUU | Upstream (-6 to -13) | Sxl‡ | [99] |
| Slo K+ channel STREX exon (mouse) | Cassette | Ca2+-dependent in neurons | Silencer (CaRRE) | CCUUGCCAUUAACCGCGcUcUUCcUcUCCUCCCAUCCACCACAUGGUUAUAG | Upstream (-53 to -1) | Unknown | [100] |
| tat intron 2 (HIV-1) | Intron retention | Variable | Silencer (ISS) | UAGUGAAUAGAGUUAGGCAGGGA | Upstream of SA7 splice site (-44 to -22) | hnRNP A1‡ | [101] |
| tau exon 10 (human) | Cassette | Aberrantly spliced in disease | Silencer (ISS) | UCACACGU | Downstream (+11 to 18) | Unknown | [102] |
| tau exon 10 (human) | Cassette | Aberrantly spliced in disease | Enhancer (ISM) | CCCAUGCG | Downstream (+19 to 26) | Unknown | [103] |
| Thyroid hormone receptor exon 9 (rat) | Alternative 5' splice site | Tissue and developmental stage-specific | Enhancer (SEα2) | GGCGGCCAGAgggUGUGCggagcugguggggaggagCUUggagagaagggaCAAAGCUgggggCUgagggagaaCCCCCA | Downstream (+130 to 210) | SF2/ASF‡, hnRNP H‡ | [104,105] |
| transformer exon 2 (Drosophila) | Alternative 3' splice site | Sex-specific | Enhancer | Not published | Downstream of non-sex-specific 3 splice site (about 40 nucleotides) | Unknown | [106] |
| transformer exon 2 (Drosophila) | Alternative 3' splice site | Sex-specific | Silencer of non-sex-specific 3 splice site | UUUUUUUU | Upstream of non-sex-specific 3 splice site (-4 to -11) | Sxl‡, U2 snRNP‡ | [107,108] |
| α-tropomyosin exons 2/3 (rat) | Mutually exclusive exons | Smooth muscle-specific | Silencer (URE) | aucacgcugccugcugcaCCCCACCCCCUUCCCCCUUCCUUCCCCCCACCCCCGUACUCCACUGCCAACUCCC | Upstream of exon 3 (-75 to -1) | Unknown | [109,110,111] |
| α-tropomyosin exons 2/3 (rat) | Mutually exclusive exons | Smooth muscle-specific | Silencer (DRE) | CUGGAUGCCGCCUCUGCUGCUGCGCACAUUUCAUUUAUAUUCUGUCCUUUCCCCUUUUUCUCCUCUUCUUUACCUCCUCCCCUUUGGUUG | Downstream of exon 3 (+142 to 231) | PTB‡ | [109,110,111] |
| β-tropomyosin exons 6A/6B (chicken) | Mutually exclusive exons | Skeletal muscle-specific | Enhancer (S4) | CCCCUCUCUCUAUCGCUGUCUCUUGAGCCACGC | Downstream of exon 6A (+37 to 69) | ASF/SF2, SC35, PTB, hnRNP K | [112,113,114,115] |
| β-tropomyosin exons 6A/6B (chicken) | Mutually exclusive exons | Skeletal muscle-specific | Enhancer (IVS B7) | GCUGGGGCUGGGCAGAGCGCGCAGGGUUGAGGGGAGCAGGGUCCUUCACUGGGGUGAA | Downstream of exon 6B (+19 to 76) | TLS‡ | [116,117] |
| β-tropomyosin exons 6/7 (rat) | Mutually exclusive exons | Striated muscle-specific | Silencer (IRE) | AACCCCACCCCCUCACCCCGUCGUCGCGCCACCCCACUGUCUCACCUCACUGUGCCCUCACGCUCCAUCCUGCCACACGCCCCUGCAG | Upstream of exon 7 (-88 to -1) | PTB‡, Sam68, FBP | [118,119] |
*Elements listed may not have been shown to regulate the specificity of alternative splicing. † Sequences that have been shown to be important for element function but that have not yet been demonstrated to bind to specific trans-acting factors are shown in lower-case letters. ‡ Indicates that the factor has been shown to bind directly to the element (for example, by ultraviolet-induced crosslinking) and has had binding confirmed (for example, by mutational analysis). Specific binding sequences for trans-actingfactors are indicated in bold, italics or underlined when known.