Table 2 |
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|
Known auxiliary intronic elements that regulate alternative splicing |
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| 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] |
|
|
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|
*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. |
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|
Ladd and Cooper Genome Biology 2002 3:reviews0008.1 doi:10.1186/gb-2002-3-11-reviews0008 |
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