Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2

Genes and Development - Tập 22 Số 18 - Trang 2550-2563 - 2008
Chaolin Zhang1, Zuo‐Feng Zhang2, John C. Castle3, Shuying Sun4,5, Jason M. Johnson3, Adrian R. Krainer2, Michael Q. Zhang2
1Cold Spring Harbor Laboratory Cold Spring Harbor, New York, 11724 USA
2#N##TAB##TAB##TAB##TAB# Cold Spring Harbor Laboratory#N##TAB##TAB##TAB#
3Merck
4Cold Spring Harbor Laboratory
5Stony Brook University

Tóm tắt

The precise regulation of many alternative splicing (AS) events by specific splicing factors is essential to determine tissue types and developmental stages. However, the molecular basis of tissue-specific AS regulation and the properties of splicing regulatory networks (SRNs) are poorly understood. Here we comprehensively predict the targets of the brain- and muscle-specific splicing factor Fox-1 (A2BP1) and its paralog Fox-2 (RBM9) and systematically define the corresponding SRNs genome-wide. Fox-1/2 are conserved from worm to human, and specifically recognize the RNA element UGCAUG. We integrate Fox-1/2-binding specificity with phylogenetic conservation, splicing microarray data, and additional computational and experimental characterization. We predict thousands of Fox-1/2 targets with conserved binding sites, at a false discovery rate (FDR) of ∼24%, including many validated experimentally, suggesting a surprisingly extensive SRN. The preferred position of the binding sites differs according to AS pattern, and determines either activation or repression of exon recognition by Fox-1/2. Many predicted targets are important for neuromuscular functions, and have been implicated in several genetic diseases. We also identified instances of binding site creation or loss in different vertebrate lineages and human populations, which likely reflect fine-tuning of gene expression regulation during evolution.

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Tài liệu tham khảo

10.1038/ng1985

10.1038/sj.emboj.7600918

10.1128/MCB.26.4.1209-1222.2006

Bhalla,, 2004, The de novo chromosome 16 translocations of two patients with abnormal phenotypes (mental retardation and epilepsy) disrupt the A2BP1 gene, J. Hum. Genet., 49, 308, 10.1007/s10038-004-0145-4

10.1146/annurev.biochem.72.121801.161720

10.1016/j.cell.2006.06.023

10.1101/gad.1500707

10.1101/gad.1558107

10.1093/nar/29.11.2338

10.1038/nrg775

10.1093/nar/gkm485

10.1101/gad.1643108

10.1186/gb-2003-4-9-r60

Dickins,, 2005, Probing tumor phenotypes using stable and regulated synthetic microRNA precursors, Nat. Genet., 37, 1289, 10.1038/ng1651

10.1186/gb-2007-8-6-r108

10.1093/nar/gkm569

10.1101/gad.8.13.1561

10.1261/rna.725208

10.1073/pnas.0500543102

10.1038/nature06258

10.1038/35057062

10.1261/rna.457207

10.1038/ng1136

10.1093/emboj/cdg089

10.1126/science.1090100

10.1074/jbc.271.30.17613

10.1161/01.CIR.0000066694.21510.E2

10.1038/nprot.2006.47

10.1007/s00335-001-2056-4

10.1128/MCB.01508-07

10.1038/nrn2237

Lim,, 1998, Alternative splicing of the fibronectin EIIIB exon depends on specific TGCATG repeats, Mol. Cell. Biol., 18, 3900, 10.1128/MCB.18.7.3900

10.1146/annurev.genet.32.1.279

10.1016/j.febslet.2005.02.047

10.1016/j.molcel.2007.07.015

10.1038/416499a

Martin,, 2007, Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism, Am. J. Med. Genet. B Neuropsychiatr. Genet., 144B, 869, 10.1002/ajmg.b.30530

10.1038/embor.2008.44

10.1186/gb-2007-8-8-r159

McKusick, V.A. (1998) Mendelian inheritance in man. A catalog of human genes and genetic disorders (Johns Hopkins University Press, Baltimore).

10.1016/S0168-9525(00)02004-7

10.1101/gr.6761107

10.1093/nar/gki210

10.1261/rna.868008

10.1093/nar/gki338

10.1210/me.16.3.459

10.1074/jbc.M511556200

10.1126/science.1138659

10.1038/nature06340

Sugnet,, 2004, Transcriptome and genome conservation of alternative splicing events in humans and mice, Pac. Symp. Biocomput., 2004, 66

10.1371/journal.pcbi.0020004

10.1093/nar/gkh030

10.1016/j.ymeth.2005.07.018

10.1038/ng1610

10.1038/nature05304

10.1128/MCB.25.22.10005-10016.2005

10.1101/gr.6017807

10.1073/pnas.0409742102

10.1371/journal.pgen.0030085

10.1073/pnas.0703773104

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Genes and Development

Tập 22 Số 18

2550-2563

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