Home LiteratureArticle Details
PMID: 19136955 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

An RNA code for the FOX2 splicing regulator revealed by mapping RNA-protein interactions in stem cells.

Nature structural & molecular biology ·Vol. 16 ·No. 2 ·2009-02-00 ·Pages 130-7

Yeo GW, Coufal NG, Liang TY, Peng GE, Fu XD, Gage FH

Abstract

The elucidation of a code for regulated splicing has been a long-standing goal in understanding the control of post-transcriptional gene expression events that are crucial for cell survival, differentiation and development. We decoded functional RNA elements in vivo by constructing an RNA map for the cell type-specific splicing regulator FOX2 (also known as RBM9) via cross-linking immunoprecipitation coupled with high-throughput sequencing (CLIP-seq) in human embryonic stem cells. The map identified a large cohort of specific FOX2 targets, many of which are themselves splicing regulators, and comparison between the FOX2 binding profile and validated splicing events revealed a general rule for FOX2-regulated exon inclusion or skipping in a position-dependent manner. These findings suggest that FOX2 functions as a critical regulator of a splicing network, and we further show that FOX2 is important for the survival of human embryonic stem cells.

MeSH Terms
Alternative Splicing Cell Survival Embryonic Stem Cells/metabolism Exons Humans Immunoprecipitation RNA Splice Sites RNA Splicing Factors RNA-Binding Proteins/metabolism Repressor Proteins/metabolism Sequence Analysis, RNA
Chemicals
RBFOX2 protein, human RNA Splice Sites RNA Splicing Factors RNA-Binding Proteins Repressor Proteins
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Yeo Gene W
Crick-Jacobs Center for Theoretical and Computational Biology, Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA. geneyeo@ucsd.edu
Coufal Nicole G
Liang Tiffany Y
Peng Grace E
Fu Xiang-Dong
Gage Fred H
References (31)
31 references, click to expand
  1. Direct isolation of human central nervous system stem cells.
    Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14720-5 PMID: 11121071
  2. Homologues of the Caenorhabditis elegans Fox-1 protein are neuronal splicing regulators in mammals.
    Mol Cell Biol. 2005 Nov;25(22):10005-16 PMID: 16260614
  3. Identification and analysis of alternative splicing events conserved in human and mouse.
    Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2850-5 PMID: 15708978
  4. Computational analysis of candidate intron regulatory elements for tissue-specific alternative pre-mRNA splicing.
    Nucleic Acids Res. 2001 Jun 1;29(11):2338-48 PMID: 11376152
  5. Rapid, simultaneous measurement of DNA, protein, and cell volume in single cells from large mammalian cell populations.
    J Cell Biol. 1973 Dec;59(3):766-71 PMID: 4128323
  6. Intronic sequences flanking alternatively spliced exons are conserved between human and mouse.
    Genome Res. 2003 Jul;13(7):1631-7 PMID: 12840041
  7. Embryonic stem cell differentiation: emergence of a new era in biology and medicine.
    Genes Dev. 2005 May 15;19(10):1129-55 PMID: 15905405
  8. Predictive identification of exonic splicing enhancers in human genes.
    Science. 2002 Aug 9;297(5583):1007-13 PMID: 12114529
  9. A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons.
    Genes Dev. 2007 Jul 1;21(13):1636-52 PMID: 17606642
  10. Molecular basis of RNA recognition by the human alternative splicing factor Fox-1.
    EMBO J. 2006 Jan 11;25(1):163-73 PMID: 16362037
  11. Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2.
    Genes Dev. 2008 Sep 15;22(18):2550-63 PMID: 18794351
  12. Fox-2 splicing factor binds to a conserved intron motif to promote inclusion of protein 4.1R alternative exon 16.
    J Biol Chem. 2006 May 5;281(18):12468-74 PMID: 16537540
  13. Intronic alternative splicing regulators identified by comparative genomics in nematodes.
    PLoS Comput Biol. 2006 Jul 14;2(7):e86 PMID: 16839192
  14. Comparative analysis identifies exonic splicing regulatory sequences--The complex definition of enhancers and silencers.
    Mol Cell. 2006 Jun 23;22(6):769-781 PMID: 16793546
  15. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model.
    Nat Neurosci. 2005 Oct;8(10):1343-9 PMID: 16136043
  16. Embryonic stem cell lines derived from human blastocysts.
    Science. 1998 Nov 6;282(5391):1145-7 PMID: 9804556
  17. CLIP identifies Nova-regulated RNA networks in the brain.
    Science. 2003 Nov 14;302(5648):1212-5 PMID: 14615540
  18. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes.
    Genome Res. 2005 Aug;15(8):1034-50 PMID: 16024819
  19. Stem cells may reshape the prospect of Parkinson's disease therapy.
    Brain Res Mol Brain Res. 2005 Mar 24;134(1):34-51 PMID: 15790528
  20. Mechanisms of alternative pre-messenger RNA splicing.
    Annu Rev Biochem. 2003;72:291-336 PMID: 12626338
  21. An RNA map predicting Nova-dependent splicing regulation.
    Nature. 2006 Nov 30;444(7119):580-6 PMID: 17065982
  22. YOPRO-1 permits cytofluorometric analysis of programmed cell death (apoptosis) without interfering with cell viability.
    J Immunol Methods. 1995 Sep 25;185(2):249-58 PMID: 7561136
  23. Post-transcriptional gene regulation: from genome-wide studies to principles.
    Cell Mol Life Sci. 2008 Mar;65(5):798-813 PMID: 18043867
  24. Alternative splicing events identified in human embryonic stem cells and neural progenitors.
    PLoS Comput Biol. 2007 Oct;3(10):1951-67 PMID: 17967047
  25. Fox-2 mediates epithelial cell-specific fibroblast growth factor receptor 2 exon choice.
    Mol Cell Biol. 2006 Feb;26(4):1209-22 PMID: 16449636
  26. The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing.
    Mol Cell. 2007 Aug 3;27(3):435-48 PMID: 17679093
  27. A vertebrate RNA-binding protein Fox-1 regulates tissue-specific splicing via the pentanucleotide GCAUG.
    EMBO J. 2003 Feb 17;22(4):905-12 PMID: 12574126
  28. Rapid flow cytofluorometric analysis of mammalian cell cycle by propidium iodide staining.
    J Cell Biol. 1975 Jul;66(1):188-93 PMID: 49354
  29. Tissue-dependent isoforms of mammalian Fox-1 homologs are associated with tissue-specific splicing activities.
    Nucleic Acids Res. 2005 Apr 11;33(7):2078-89 PMID: 15824060
  30. Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing.
    Nat Methods. 2007 Aug;4(8):651-7 PMID: 17558387
  31. Discovery and analysis of evolutionarily conserved intronic splicing regulatory elements.
    PLoS Genet. 2007 May 25;3(5):e85 PMID: 17530930
Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb.1545
Email
geneyeo@ucsd.edu
Published
2009-02-00
Epub
2009-00-11
Pages
130-7
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC2735254
Subset
IM
Grants
NHGRI NIH HHS · HG004659 · United States
NCRR NIH HHS · S10 RR025547-01 · United States
NIGMS NIH HHS · R01 GM049369-16 · United States
NIGMS NIH HHS · GM049369 · United States
NHGRI NIH HHS · R01 HG004659-02 · United States
NIGMS NIH HHS · R01 GM049369 · United States
NHGRI NIH HHS · R01 HG004659-01 · United States
NHGRI NIH HHS · R01 HG004659 · United States
NCRR NIH HHS · S10 RR025547 · United States
External Links
PubMed source DOI: 10.1038/nsmb.1545 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2