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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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Differential Exon/Intron Association Suggests That Certain RNA-Binding Proteins Bind Their Targets during Specific Stages in Their LivesThe relative enrichment of exons and introns in association with RBPs (columns) is represented using a color scale. Results are shown for RBPs that associated substantially more or less strongly with exons or introns than with RNAs overall (mean enrichment of exons from intron-containing genes or introns 25% above or below the median IP enrichment of all RNAs, respectively).
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pbio-0060255-g003: Differential Exon/Intron Association Suggests That Certain RNA-Binding Proteins Bind Their Targets during Specific Stages in Their LivesThe relative enrichment of exons and introns in association with RBPs (columns) is represented using a color scale. Results are shown for RBPs that associated substantially more or less strongly with exons or introns than with RNAs overall (mean enrichment of exons from intron-containing genes or introns 25% above or below the median IP enrichment of all RNAs, respectively).

Mentions: To test this idea, we compared the enrichment of intron and exon sequences in association with RBPs. For the approximately 120 intron/exon probe pairs for which our data were most consistently reliable, the relative enrichment profiles vary greatly among RBPs (Figure 3 and Text S6). For example, Cbc2 (a component of the heterodimeric nuclear cap-binding protein) and Pab1 were preferentially associated with both intron-containing transcripts and mature mRNAs derived from intron-containing transcripts (Figure 3). Cbc2 was strongly associated with intron-containing transcripts (mean enrichment of intronic sequences = 6.8), and also, but to a considerably lesser extent, with exon sequences from intron-derived transcripts (mean enrichment of exonic sequences = 1.5). These results are consistent with Cbc2 binding during transcription, prior to splicing, and being displaced shortly after the mature mRNA reaches the cytoplasm [68,69]. The enrichment of intron-related transcripts and the paucity of significantly enriched mature mRNAs suggest that most mRNAs spend only a very small fraction of their lives in the nucleus. That Pab1, the major poly(A) binding protein, associated with intron-containing transcripts (mean enrichment of intronic sequences = 1.5), as well as sequences from exons (mean enrichment of exonic sequences = 3.9), is consistent with most splicing occurring after poly(A) tail addition [70].


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)

Differential Exon/Intron Association Suggests That Certain RNA-Binding Proteins Bind Their Targets during Specific Stages in Their LivesThe relative enrichment of exons and introns in association with RBPs (columns) is represented using a color scale. Results are shown for RBPs that associated substantially more or less strongly with exons or introns than with RNAs overall (mean enrichment of exons from intron-containing genes or introns 25% above or below the median IP enrichment of all RNAs, respectively).
© Copyright Policy
Related In: Results  -  Collection

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

pbio-0060255-g003: Differential Exon/Intron Association Suggests That Certain RNA-Binding Proteins Bind Their Targets during Specific Stages in Their LivesThe relative enrichment of exons and introns in association with RBPs (columns) is represented using a color scale. Results are shown for RBPs that associated substantially more or less strongly with exons or introns than with RNAs overall (mean enrichment of exons from intron-containing genes or introns 25% above or below the median IP enrichment of all RNAs, respectively).
Mentions: To test this idea, we compared the enrichment of intron and exon sequences in association with RBPs. For the approximately 120 intron/exon probe pairs for which our data were most consistently reliable, the relative enrichment profiles vary greatly among RBPs (Figure 3 and Text S6). For example, Cbc2 (a component of the heterodimeric nuclear cap-binding protein) and Pab1 were preferentially associated with both intron-containing transcripts and mature mRNAs derived from intron-containing transcripts (Figure 3). Cbc2 was strongly associated with intron-containing transcripts (mean enrichment of intronic sequences = 6.8), and also, but to a considerably lesser extent, with exon sequences from intron-derived transcripts (mean enrichment of exonic sequences = 1.5). These results are consistent with Cbc2 binding during transcription, prior to splicing, and being displaced shortly after the mature mRNA reaches the cytoplasm [68,69]. The enrichment of intron-related transcripts and the paucity of significantly enriched mature mRNAs suggest that most mRNAs spend only a very small fraction of their lives in the nucleus. That Pab1, the major poly(A) binding protein, associated with intron-containing transcripts (mean enrichment of intronic sequences = 1.5), as well as sequences from exons (mean enrichment of exonic sequences = 3.9), is consistent with most splicing occurring after poly(A) tail addition [70].

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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