Ab initio identification of functionally interacting pairs of cis-regulatory elements.
Cooperatively acting pairs of cis-regulatory elements play important roles in many biological processes. Here, we describe a statistical approach, compositionally orthogonalized co-occurrence analysis (coCOA) that detects pairs of oligonucleotides that preferentially co-occur in pairs of sequence regions, controlling for correlations between the compositions of the analyzed regions. coCOA identified three clusters of oligonucleotide pairs that frequently co-occur at 5' and 3' ends of human and mouse introns. The largest cluster involved GC-rich sequences at the 5' ends of introns that co-occur and are co-conserved with specific AU-rich sequences near intron 3' ends. These motifs are preferentially conserved when they occur together, as measured by a new co-conservation measure, supporting common in vivo function. These motif pairs are also enriched in introns flanking alternative "cassette" exons, suggesting a role in silencing of intervening exons, and we showed that these motifs can cooperatively silence splicing of an intervening exon in a splicing reporter assay. This approach can be easily generalized to problems beyond RNA splicing.
Friedman
Brad A
BA
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. friedm@mcb.harvard.edu
Stadler
Michael B
MB
Shomron
Noam
N
Ding
Ye
Y
Burge
Christopher B
CB
D000818:Animals; D001483:Base Sequence; D019295:Computational Biology; D017124:Conserved Sequence; D005091:Exons; D020862:GC Rich Sequence / Q000235:genetics; D006801:Humans; D007438:Introns; D051379:Mice; D012326:RNA Splicing; D012045:Regulatory Sequences, Nucleic Acid; D017423:Sequence Analysis, RNA
Nucleic Acids Res. 2007;35(10):3203-13
17452354
Genes Dev. 1999 Apr 1;13(7):851-63
10197985
Mol Cell Biol. 1997 Apr;17(4):2143-50
9121463
Science. 1993 Oct 8;262(5131):208-14
8211139
Mol Cell. 1998 Dec;2(6):773-85
9885565
RNA. 2002 Mar;8(3):265-78
12003487
Genome Res. 2002 Jun;12(6):996-1006
12045153
Science. 2002 Aug 9;297(5583):1007-13
12114529
Genes Dev. 2004 Jun 1;18(11):1241-50
15145827
PLoS Comput Biol. 2005 Dec;1(7):e69
16355253
Chromosome Res. 2000;8(8):737-46
11196136
Nature. 2005 Mar 17;434(7031):338-45
15735639
Mol Cell Biol. 1993 Dec;13(12):7652-65
8246982
Genome Biol. 2004;5(8):R56
15287978
Genome Biol. 2002 Oct 23;3(11):reviews0008
12429065
J Comput Biol. 2004;11(2-3):377-94
15285897
Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2850-5
15708978
Cell. 2004 Dec 17;119(6):831-45
15607979
J Biol Chem. 1993 Apr 25;268(12):8881-7
8473331
EMBO J. 2005 Apr 20;24(8):1608-20
15933722
Annu Rev Biochem. 2003;72:291-336
12626338
Nature. 2007 Apr 19;446(7138):926-9
17361132
Hum Mol Genet. 2004 Mar 1;13(5):509-24
14709600
RNA. 2002 Aug;8(8):1078-89
12212851
Genome Res. 2005 Jun;15(6):768-79
15930489
Proc Int Conf Intell Syst Mol Biol. 1994;2:28-36
7584402
Nucleic Acids Res. 2002 Oct 1;30(19):4278-84
12364607
Genetics. 2005 Jun;170(2):661-74
15802507
Genes Dev. 1998 Jul 1;12(13):1998-2012
9649504
Mol Cell Biol. 2000 Sep;20(17):6287-99
10938105
Genome Res. 2006 Oct;16(10):1299-309
16954542
Nat Genet. 2001 Oct;29(2):153-9
11547334
Mol Cell. 2004 Jan 16;13(1):91-100
14731397
Cell. 2005 Jan 14;120(1):15-20
15652477
FEBS Lett. 2004 Nov 5;577(1-2):134-40
15527774
Genome Res. 2008 Mar;18(3):477-88
18256240
Hum Mol Genet. 2005 Jun 1;14(11):1559-68
15857856
Mol Cell. 2006 Jul 7;23(1):61-70
16797197
Bioinformatics. 2001 Jul;17(7):608-21
11448879
Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15700-5
15505203
Nat Rev Mol Cell Biol. 2005 May;6(5):386-98
15956978
Genome Res. 2004 Oct;14(10A):1967-74
15466295
Hum Mol Genet. 2006 Aug 15;15(16):2490-508
16825284
EMBO J. 1999 Apr 1;18(7):1939-52
10202157