Home LiteratureArticle Details
PMID: 21723170 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability.

Molecular cell ·Vol. 43 ·No. 3 ·2011-08-05 ·Pages 327-39

Mukherjee N, Corcoran DL, Nusbaum JD, Reid DW, Georgiev S, Hafner M, Ascano M, Tuschl T, Ohler U, Keene JD

Abstract

RNA-binding proteins coordinate the fates of multiple RNAs, but the principles underlying these global interactions remain poorly understood. We elucidated regulatory mechanisms of the RNA-binding protein HuR, by integrating data from diverse high-throughput targeting technologies, specifically PAR-CLIP, RIP-chip, and whole-transcript expression profiling. The number of binding sites per transcript, degree of HuR association, and degree of HuR-dependent RNA stabilization were positively correlated. Pre-mRNA and mature mRNA containing both intronic and 3' UTR binding sites were more highly stabilized than transcripts with only 3' UTR or only intronic binding sites, suggesting that HuR couples pre-mRNA processing with mature mRNA stability. We also observed HuR-dependent splicing changes and substantial binding of HuR in polypyrimidine tracts of pre-mRNAs. Comparison of the spatial patterns surrounding HuR and miRNA binding sites provided functional evidence for HuR-dependent antagonism of proximal miRNA-mediated repression. We conclude that HuR coordinates gene expression outcomes at multiple interconnected steps of RNA processing.

MeSH Terms
Amino Acid Motifs Antigens, Surface/chemistry,metabolism,physiology Binding Sites Computational Biology ELAV Proteins ELAV-Like Protein 1 Gene Expression Regulation HEK293 Cells Humans MicroRNAs/metabolism,physiology RNA Precursors/metabolism RNA Processing, Post-Transcriptional RNA Stability RNA, Messenger/metabolism RNA-Binding Proteins/chemistry,metabolism,physiology Software
Chemicals
Antigens, Surface ELAV Proteins ELAV-Like Protein 1 ELAVL1 protein, human MicroRNAs RNA Precursors RNA, Messenger RNA-Binding Proteins
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Mukherjee Neelanjan
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Corcoran David L
Nusbaum Jeffrey D
Reid David W
Georgiev Stoyan
Hafner Markus
Ascano Manuel
Tuschl Thomas
Ohler Uwe
Keene Jack D
References (50)
50 references, click to expand
  1. The elav gene product of Drosophila, required in neurons, has three RNP consensus motifs.
    Science. 1988 Dec 16;242(4885):1570-2 PMID: 3144044
  2. From birth to death: the complex lives of eukaryotic mRNAs.
    Science. 2005 Sep 2;309(5740):1514-8 PMID: 16141059
  3. CLIP identifies Nova-regulated RNA networks in the brain.
    Science. 2003 Nov 14;302(5648):1212-5 PMID: 14615540
  4. Applications for protein sequence-function evolution data: mRNA/protein expression analysis and coding SNP scoring tools.
    Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W645-50 PMID: 16912992
  5. Evidence for reassociation of RNA-binding proteins after cell lysis: implications for the interpretation of immunoprecipitation analyses.
    RNA. 2004 Nov;10(11):1692-4 PMID: 15388877
  6. Specific protein domains mediate cooperative assembly of HuR oligomers on AU-rich mRNA-destabilizing sequences.
    J Biol Chem. 2007 Jul 20;282(29):20948-59 PMID: 17517897
  7. Alternative splicing in the differentiation of human embryonic stem cells into cardiac precursors.
    PLoS Comput Biol. 2009 Nov;5(11):e1000553 PMID: 19893621
  8. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  9. Diverse molecular functions of Hu proteins.
    Cell Mol Life Sci. 2008 Oct;65(20):3168-81 PMID: 18581050
  10. The ribonome: a dominant force in co-ordinating gene expression.
    Biol Cell. 2009 Mar;101(3):169-81 PMID: 19152504
  11. Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs.
    EMBO J. 1998 Jun 15;17(12):3448-60 PMID: 9628880
  12. HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to Elav and Sex-lethal.
    Cell. 1991 Oct 18;67(2):325-33 PMID: 1655278
  13. Linking splicing to Pol II transcription stabilizes pre-mRNAs and influences splicing patterns.
    PLoS Biol. 2006 Jun;4(6):e147 PMID: 16640457
  14. mRNA openers and closers: modulating AU-rich element-controlled mRNA stability by a molecular switch in mRNA secondary structure.
    Chembiochem. 2004 Oct 4;5(10):1432-47 PMID: 15457527
  15. Ectopic expression of Hel-N1, an RNA-binding protein, increases glucose transporter (GLUT1) expression in 3T3-L1 adipocytes.
    Mol Cell Biol. 1997 Feb;17(2):954-62 PMID: 9001249
  16. Analysis of the stimulatory effect of splicing on mRNA production and utilization in mammalian cells.
    RNA. 2003 May;9(5):618-30 PMID: 12702820
  17. Diverse RNA-binding proteins interact with functionally related sets of RNAs, suggesting an extensive regulatory system.
    PLoS Biol. 2008 Oct 28;6(10):e255 PMID: 18959479
  18. RNA stabilization by the AU-rich element binding protein, HuR, an ELAV protein.
    EMBO J. 1998 Jun 15;17(12):3461-70 PMID: 9628881
  19. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
    Genome Biol. 2009;10(3):R25 PMID: 19261174
  20. Control of thymic T cell maturation, deletion and egress by the RNA-binding protein HuR.
    J Immunol. 2009 Jun 1;182(11):6779-88 PMID: 19454673
  21. Comparison of intron-dependent and intron-independent gene expression.
    Mol Cell Biol. 1988 Oct;8(10):4395-405 PMID: 3185553
  22. Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators.
    Proc Natl Acad Sci U S A. 1986 Mar;83(6):1670-4 PMID: 2419912
  23. An extensive network of coupling among gene expression machines.
    Nature. 2002 Apr 4;416(6880):499-506 PMID: 11932736
  24. Understanding splicing regulation through RNA splicing maps.
    Trends Genet. 2011 Mar;27(3):89-97 PMID: 21232811
  25. Hu proteins regulate polyadenylation by blocking sites containing U-rich sequences.
    J Biol Chem. 2007 Jan 26;282(4):2203-10 PMID: 17127772
  26. HuR and mRNA stability.
    Cell Mol Life Sci. 2001 Feb;58(2):266-77 PMID: 11289308
  27. Identification of a target RNA motif for RNA-binding protein HuR.
    Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2987-92 PMID: 14981256
  28. Eukaryotic mRNPs may represent posttranscriptional operons.
    Mol Cell. 2002 Jun;9(6):1161-7 PMID: 12086614
  29. Relief of microRNA-mediated translational repression in human cells subjected to stress.
    Cell. 2006 Jun 16;125(6):1111-24 PMID: 16777601
  30. Post-transcriptional gene regulation: from genome-wide studies to principles.
    Cell Mol Life Sci. 2008 Mar;65(5):798-813 PMID: 18043867
  31. Hel-N1: an autoimmune RNA-binding protein with specificity for 3' uridylate-rich untranslated regions of growth factor mRNAs.
    Mol Cell Biol. 1993 Jun;13(6):3494-504 PMID: 8497264
  32. Structural basis for recognition of AU-rich element RNA by the HuD protein.
    Nat Struct Biol. 2001 Feb;8(2):141-5 PMID: 11175903
  33. RIP-Chip: the isolation and identification of mRNAs, microRNAs and protein components of ribonucleoprotein complexes from cell extracts.
    Nat Protoc. 2006;1(1):302-7 PMID: 17406249
  34. Pre-mRNA processing reaches back to transcription and ahead to translation.
    Cell. 2009 Feb 20;136(4):688-700 PMID: 19239889
  35. Hu antigen R (HuR) functions as an alternative pre-mRNA splicing regulator of Fas apoptosis-promoting receptor on exon definition.
    J Biol Chem. 2008 Jul 4;283(27):19077-84 PMID: 18463097
  36. RNA regulons: coordination of post-transcriptional events.
    Nat Rev Genet. 2007 Jul;8(7):533-43 PMID: 17572691
  37. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP.
    Cell. 2010 Apr 2;141(1):129-41 PMID: 20371350
  38. Coordinated posttranscriptional mRNA population dynamics during T-cell activation.
    Mol Syst Biol. 2009;5:288 PMID: 19638969
  39. Evidence-ranked motif identification.
    Genome Biol. 2010;11(2):R19 PMID: 20156354
  40. RNAcontext: a new method for learning the sequence and structure binding preferences of RNA-binding proteins.
    PLoS Comput Biol. 2010 Jul 01;6:e1000832 PMID: 20617199
  41. Ensembl 2007.
    Nucleic Acids Res. 2007 Jan;35(Database issue):D610-7 PMID: 17148474
  42. The RNA-binding protein Elavl1/HuR is essential for placental branching morphogenesis and embryonic development.
    Mol Cell Biol. 2009 May;29(10):2762-76 PMID: 19307312
  43. Identifying mRNA subsets in messenger ribonucleoprotein complexes by using cDNA arrays.
    Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14085-90 PMID: 11121017
  44. HuR recruits let-7/RISC to repress c-Myc expression.
    Genes Dev. 2009 Aug 1;23(15):1743-8 PMID: 19574298
  45. Systematic analysis of posttranscriptional gene expression.
    Wiley Interdiscip Rev Syst Biol Med. 2010 Mar-Apr;2(2):162-180 PMID: 20836020
  46. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation.
    Cell. 1986 Aug 29;46(5):659-67 PMID: 3488815
  47. Analysis of turnover and translation regulatory RNA-binding protein expression through binding to cognate mRNAs.
    Mol Cell Biol. 2007 Sep;27(18):6265-78 PMID: 17620417
  48. Identification of transformation-related pathways in a breast epithelial cell model using a ribonomics approach.
    Cancer Res. 2008 Oct 1;68(19):7730-5 PMID: 18829526
  49. iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution.
    Nat Struct Mol Biol. 2010 Jul;17(7):909-15 PMID: 20601959
  50. Ribonucleoprotein infrastructure regulating the flow of genetic information between the genome and the proteome.
    Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7018-24 PMID: 11416181
Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2011.06.007
Published
2011-08-05
Epub
2011-00-30
Pages
327-39
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3220597
Subset
IM
Grants
Howard Hughes Medical Institute · United States
NIDA NIH HHS · R01 DA030086 · United States
NIDA NIH HHS · DA030086 · United States
Databases
GEO
GSE29780
Corrections
CommentIn
PMID: 21816340
External Links
PubMed source DOI: 10.1016/j.molcel.2011.06.007 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: [email protected]

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