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Diverse RNA-binding proteins interact with functionally related sets of RNAs, suggesting an extensive regulatory system.

Hogan DJ, Riordan DP, Gerber AP, Herschlag D, Brown PO - PLoS Biol. (2008)

Bottom Line: These potential RNA-recognition elements were diverse in sequence, structure, and location: some were found predominantly in 3'-untranslated regions, others in 5'-untranslated regions, some in coding sequences, and many in two or more of these features.Although this study only examined a small fraction of the universe of yeast RBPs, 70% of the mRNA transcriptome had significant associations with at least one of these RBPs, and on average, each distinct yeast mRNA interacted with three of the RBPs, suggesting the potential for a rich, multidimensional network of regulation.These results strongly suggest that combinatorial binding of RBPs to specific recognition elements in mRNAs is a pervasive mechanism for multi-dimensional regulation of their post-transcriptional fate.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT
RNA-binding proteins (RBPs) have roles in the regulation of many post-transcriptional steps in gene expression, but relatively few RBPs have been systematically studied. We searched for the RNA targets of 40 proteins in the yeast Saccharomyces cerevisiae: a selective sample of the approximately 600 annotated and predicted RBPs, as well as several proteins not annotated as RBPs. At least 33 of these 40 proteins, including three of the four proteins that were not previously known or predicted to be RBPs, were reproducibly associated with specific sets of a few to several hundred RNAs. Remarkably, many of the RBPs we studied bound mRNAs whose protein products share identifiable functional or cytotopic features. We identified specific sequences or predicted structures significantly enriched in target mRNAs of 16 RBPs. These potential RNA-recognition elements were diverse in sequence, structure, and location: some were found predominantly in 3'-untranslated regions, others in 5'-untranslated regions, some in coding sequences, and many in two or more of these features. Although this study only examined a small fraction of the universe of yeast RBPs, 70% of the mRNA transcriptome had significant associations with at least one of these RBPs, and on average, each distinct yeast mRNA interacted with three of the RBPs, suggesting the potential for a rich, multidimensional network of regulation. These results strongly suggest that combinatorial binding of RBPs to specific recognition elements in mRNAs is a pervasive mechanism for multi-dimensional regulation of their post-transcriptional fate.

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Diverse Sequence Motifs Enriched in mRNAs Bound by Specific RNA-Binding ProteinsA pictogram (http://genes.mit.edu/pictogram.html) represents the regular expression patterns defined for FIRE motifs or the preferred base composition of the position-specific scoring matrices for REFINE motifs. For each motif, the negative log10p-value of the significance of genome-wide enrichment for motif sites in targets is represented (using a color scale) for segments of its mRNA targets (5′ = 200 bases upstream of start codon, CDS = protein coding sequence, 3′ = 200 bases downstream of stop codon). Arrows indicate motifs with a forward strand bias, i.e., the reverse complements of the motifs are not significantly enriched (p > 10−4 based on the hypergeometric distribution) in targets. “Cons” indicates the negative log10p-value measuring whether motif sites in targets are more likely to be conserved in orthologous sequence alignments in S. bayanus than are motif sites occurring in nontargets, based on the hypergeometric distribution. Asterisks (*) denote motifs matching previously described RNA-binding elements (details in text). Exact data values and full descriptions of all motifs are presented in Table S4.
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pbio-0060255-g005: Diverse Sequence Motifs Enriched in mRNAs Bound by Specific RNA-Binding ProteinsA pictogram (http://genes.mit.edu/pictogram.html) represents the regular expression patterns defined for FIRE motifs or the preferred base composition of the position-specific scoring matrices for REFINE motifs. For each motif, the negative log10p-value of the significance of genome-wide enrichment for motif sites in targets is represented (using a color scale) for segments of its mRNA targets (5′ = 200 bases upstream of start codon, CDS = protein coding sequence, 3′ = 200 bases downstream of stop codon). Arrows indicate motifs with a forward strand bias, i.e., the reverse complements of the motifs are not significantly enriched (p > 10−4 based on the hypergeometric distribution) in targets. “Cons” indicates the negative log10p-value measuring whether motif sites in targets are more likely to be conserved in orthologous sequence alignments in S. bayanus than are motif sites occurring in nontargets, based on the hypergeometric distribution. Asterisks (*) denote motifs matching previously described RNA-binding elements (details in text). Exact data values and full descriptions of all motifs are presented in Table S4.

Mentions: Using stringent statistical criteria based on randomized simulations (details in Materials and Methods), we identified a total of 60 candidate RNA regulatory motifs significantly associated with 21 different RBPs; 35 motifs (for 21 RBPs) were predicted by REFINE, and 25 motifs (for 13 RBPs) were predicted by FIRE (Table S4). Since the same motifs were often predicted by both programs for the same RBP or for different RBPs with significantly overlapping target sets, we manually grouped motifs with similar consensus sequences and origins into classes (Table S4). We then included only the most significant motif from each class and for each RBP, resulting in a set of 14 nonredundant RNA motifs predicted with high confidence (Figure 5). We also evaluated the predicted RNA motifs by testing whether motif sites occurring in targets were more likely to be conserved than sites in nontargets, and whether they exhibited a forward strand bias by testing for significant enrichment of the reverse complementary motif in RBP targets (Table S4).


Diverse RNA-binding proteins interact with functionally related sets of RNAs, suggesting an extensive regulatory system.

Hogan DJ, Riordan DP, Gerber AP, Herschlag D, Brown PO - PLoS Biol. (2008)

Diverse Sequence Motifs Enriched in mRNAs Bound by Specific RNA-Binding ProteinsA pictogram (http://genes.mit.edu/pictogram.html) represents the regular expression patterns defined for FIRE motifs or the preferred base composition of the position-specific scoring matrices for REFINE motifs. For each motif, the negative log10p-value of the significance of genome-wide enrichment for motif sites in targets is represented (using a color scale) for segments of its mRNA targets (5′ = 200 bases upstream of start codon, CDS = protein coding sequence, 3′ = 200 bases downstream of stop codon). Arrows indicate motifs with a forward strand bias, i.e., the reverse complements of the motifs are not significantly enriched (p > 10−4 based on the hypergeometric distribution) in targets. “Cons” indicates the negative log10p-value measuring whether motif sites in targets are more likely to be conserved in orthologous sequence alignments in S. bayanus than are motif sites occurring in nontargets, based on the hypergeometric distribution. Asterisks (*) denote motifs matching previously described RNA-binding elements (details in text). Exact data values and full descriptions of all motifs are presented in Table S4.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2573929&req=5

pbio-0060255-g005: Diverse Sequence Motifs Enriched in mRNAs Bound by Specific RNA-Binding ProteinsA pictogram (http://genes.mit.edu/pictogram.html) represents the regular expression patterns defined for FIRE motifs or the preferred base composition of the position-specific scoring matrices for REFINE motifs. For each motif, the negative log10p-value of the significance of genome-wide enrichment for motif sites in targets is represented (using a color scale) for segments of its mRNA targets (5′ = 200 bases upstream of start codon, CDS = protein coding sequence, 3′ = 200 bases downstream of stop codon). Arrows indicate motifs with a forward strand bias, i.e., the reverse complements of the motifs are not significantly enriched (p > 10−4 based on the hypergeometric distribution) in targets. “Cons” indicates the negative log10p-value measuring whether motif sites in targets are more likely to be conserved in orthologous sequence alignments in S. bayanus than are motif sites occurring in nontargets, based on the hypergeometric distribution. Asterisks (*) denote motifs matching previously described RNA-binding elements (details in text). Exact data values and full descriptions of all motifs are presented in Table S4.
Mentions: Using stringent statistical criteria based on randomized simulations (details in Materials and Methods), we identified a total of 60 candidate RNA regulatory motifs significantly associated with 21 different RBPs; 35 motifs (for 21 RBPs) were predicted by REFINE, and 25 motifs (for 13 RBPs) were predicted by FIRE (Table S4). Since the same motifs were often predicted by both programs for the same RBP or for different RBPs with significantly overlapping target sets, we manually grouped motifs with similar consensus sequences and origins into classes (Table S4). We then included only the most significant motif from each class and for each RBP, resulting in a set of 14 nonredundant RNA motifs predicted with high confidence (Figure 5). We also evaluated the predicted RNA motifs by testing whether motif sites occurring in targets were more likely to be conserved than sites in nontargets, and whether they exhibited a forward strand bias by testing for significant enrichment of the reverse complementary motif in RBP targets (Table S4).

Bottom Line: These potential RNA-recognition elements were diverse in sequence, structure, and location: some were found predominantly in 3'-untranslated regions, others in 5'-untranslated regions, some in coding sequences, and many in two or more of these features.Although this study only examined a small fraction of the universe of yeast RBPs, 70% of the mRNA transcriptome had significant associations with at least one of these RBPs, and on average, each distinct yeast mRNA interacted with three of the RBPs, suggesting the potential for a rich, multidimensional network of regulation.These results strongly suggest that combinatorial binding of RBPs to specific recognition elements in mRNAs is a pervasive mechanism for multi-dimensional regulation of their post-transcriptional fate.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT
RNA-binding proteins (RBPs) have roles in the regulation of many post-transcriptional steps in gene expression, but relatively few RBPs have been systematically studied. We searched for the RNA targets of 40 proteins in the yeast Saccharomyces cerevisiae: a selective sample of the approximately 600 annotated and predicted RBPs, as well as several proteins not annotated as RBPs. At least 33 of these 40 proteins, including three of the four proteins that were not previously known or predicted to be RBPs, were reproducibly associated with specific sets of a few to several hundred RNAs. Remarkably, many of the RBPs we studied bound mRNAs whose protein products share identifiable functional or cytotopic features. We identified specific sequences or predicted structures significantly enriched in target mRNAs of 16 RBPs. These potential RNA-recognition elements were diverse in sequence, structure, and location: some were found predominantly in 3'-untranslated regions, others in 5'-untranslated regions, some in coding sequences, and many in two or more of these features. Although this study only examined a small fraction of the universe of yeast RBPs, 70% of the mRNA transcriptome had significant associations with at least one of these RBPs, and on average, each distinct yeast mRNA interacted with three of the RBPs, suggesting the potential for a rich, multidimensional network of regulation. These results strongly suggest that combinatorial binding of RBPs to specific recognition elements in mRNAs is a pervasive mechanism for multi-dimensional regulation of their post-transcriptional fate.

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