title: Defining potentially conserved RNA regulons of homologous zinc-finger RNA-binding proteins.
abstract: BACKGROUND
  Glucose inhibition of gluconeogenic growth suppressor 2 protein (Gis2p) and zinc-finger protein 9 (ZNF9) are conserved yeast and human zinc-finger proteins. The function of yeast Gis2p is unknown, but human ZNF9 has been reported to bind nucleic acids, and mutations in the ZNF9 gene cause the neuromuscular disease myotonic dystrophy type 2. To explore the impact of these proteins on RNA regulation, we undertook a systematic analysis of the RNA targets and of the global implications for gene expression.
  
  
  RESULTS
  Hundreds of mRNAs were associated with Gis2p, mainly coding for RNA processing factors, chromatin modifiers and GTPases. Target mRNAs contained stretches of G(A/U)(A/U) trinucleotide repeats located in coding sequences, which are sufficient for binding to both Gis2p and ZNF9, thus implying strong structural conservation. Predicted ZNF9 targets belong to the same functional categories as seen in yeast, indicating functional conservation, which is further supported by complementation of the large cell-size phenotype of gis2 mutants with ZNF9. We further applied a matched-sample proteome-transcriptome analysis suggesting that Gis2p differentially coordinates expression of RNA regulons, primarily by reducing mRNA and protein levels of genes required for ribosome assembly and by selectively up-regulating protein levels of myosins.
  
  
  CONCLUSIONS
  This integrated systematic exploration of RNA targets for homologous RNA-binding proteins indicates an unexpectedly high conservation of the RNA-binding properties and of potential targets, thus predicting conserved RNA regulons. We also predict regulation of muscle-specific genes by ZNF9, adding a potential link to the myotonic dystrophy related phenotypes seen in ZNF9 mouse models.
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Scherrer
authors.forename: Christian
authors.initials: C
authors.lastname: Femmer
authors.forename: Ralph
authors.initials: R
authors.lastname: Schiess
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.forename: André P
authors.initials: AP
authors.lastname: Gerber
mesh_terms: D000595:Amino Acid Sequence; D049109:Cell Proliferation; D048429:Cell Size; D018387:Codon, Initiator; D017124:Conserved Sequence; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D016366:Open Reading Frames / Q000235:genetics; D010641:Phenotype; D020543:Proteome; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D018085:Regulon; D012091:Repetitive Sequences, Nucleic Acid; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D059467:Transcriptome; D016335:Zinc Fingers
chemical_list: C433227:CNBP protein, human; D018387:Codon, Initiator; C557900:Gis2 protein, S cerevisiae; D020543:Proteome; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins