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Discovering structural cis-regulatory elements by modeling the behaviors of mRNAs.

Foat BC, Stormo GD - Mol. Syst. Biol. (2009)

Bottom Line: In addition, we discovered six putative SCREs in flies and three in humans.We characterized the SCREs based on their condition-specific regulatory influences, the annotation of the transcripts that contain them, and their locations within transcripts.Overall, we show that modeling functional genomics data in terms of combined RNA structure and sequence motifs is an effective method for discovering the specificities and regulatory roles of RNA-binding proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Center for Genome Sciences, Washington University School of Medicine, St Louis, MO 63108, USA.

ABSTRACT
Gene expression is regulated at each step from chromatin remodeling through translation and degradation. Several known RNA-binding regulatory proteins interact with specific RNA secondary structures in addition to specific nucleotides. To provide a more comprehensive understanding of the regulation of gene expression, we developed an integrative computational approach that leverages functional genomics data and nucleotide sequences to discover RNA secondary structure-defined cis-regulatory elements (SCREs). We applied our structural cis-regulatory element detector (StructRED) to microarray and mRNA sequence data from Saccharomyces cerevisiae, Drosophila melanogaster, and Homo sapiens. We recovered the known specificities of Vts1p in yeast and Smaug in flies. In addition, we discovered six putative SCREs in flies and three in humans. We characterized the SCREs based on their condition-specific regulatory influences, the annotation of the transcripts that contain them, and their locations within transcripts. Overall, we show that modeling functional genomics data in terms of combined RNA structure and sequence motifs is an effective method for discovering the specificities and regulatory roles of RNA-binding proteins.

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Putative Drosophila structural cis-regulatory elements. (A) The structural logos of the six putative Drosophila SCREs. (B) Dm1, Dm2, Dm3, and Dm4 were detected using mRNA expression microarray data. Dm1 and Dm2 had strong negative correlations with mRNA levels over early Drosophila development. Dm1 and Dm2 did not correlate with mRNA levels in similarly treated Δsmg eggs (not shown). Dm3 and Dm4 correlated with mRNA levels changing between wild-type and Δkep1 flies (GEO accession GSE6086), suggesting that Dm3 and Dm4 may reflect the specificity of Kep1, an RNA-binding protein. (C) Dm5 and Dm6 were detected from microarray data measuring mRNA association with ribosomes in early drosophila development (Qin et al, 2007). Triangles represent increasing density of sucrose gradient fractions, corresponding to increasing numbers of ribosomes.
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f4: Putative Drosophila structural cis-regulatory elements. (A) The structural logos of the six putative Drosophila SCREs. (B) Dm1, Dm2, Dm3, and Dm4 were detected using mRNA expression microarray data. Dm1 and Dm2 had strong negative correlations with mRNA levels over early Drosophila development. Dm1 and Dm2 did not correlate with mRNA levels in similarly treated Δsmg eggs (not shown). Dm3 and Dm4 correlated with mRNA levels changing between wild-type and Δkep1 flies (GEO accession GSE6086), suggesting that Dm3 and Dm4 may reflect the specificity of Kep1, an RNA-binding protein. (C) Dm5 and Dm6 were detected from microarray data measuring mRNA association with ribosomes in early drosophila development (Qin et al, 2007). Triangles represent increasing density of sucrose gradient fractions, corresponding to increasing numbers of ribosomes.

Mentions: When we applied StructRED to the Drosophila development time courses and other microarray data, we did not specifically try to find the Smaug specificity. In fact, in addition to the Smaug SCREs, we discovered six other putative SCREs, which we have labeled Dm1 through Dm6, that have coherent supporting TFAPs and annotation (Figure 4). First, Dm1 and Dm2 were discovered from the same mRNA expression microarray time course for Drosophila embryogenesis that we discussed for the Smaug SCREs (Tadros et al, 2007). Those transcripts that contain high-affinity instances of Dm1 and Dm2 are expressed at decreasing levels as development proceeds, suggesting that they are involved in destabilizing these transcripts at specific developmental stages. Dm1- and Dm2-containing transcripts have weak enrichments for Gene Ontology categories related to development and protein transport (Supplementary Table 2). Transcripts that contain Dm1 or Dm2 display a bias for expression in the developing female reproductive system. Notably, Dm1 and Dm2 occurrences do not correlate with decreasing expression in Δsmg embryos (data not shown), suggesting that the putative destabilizing effect of Dm1 and Dm2 depends on Smaug. However, Dm1 and Dm2 do not show the translational repression activity that we see with the Smaug SCREs.


Discovering structural cis-regulatory elements by modeling the behaviors of mRNAs.

Foat BC, Stormo GD - Mol. Syst. Biol. (2009)

Putative Drosophila structural cis-regulatory elements. (A) The structural logos of the six putative Drosophila SCREs. (B) Dm1, Dm2, Dm3, and Dm4 were detected using mRNA expression microarray data. Dm1 and Dm2 had strong negative correlations with mRNA levels over early Drosophila development. Dm1 and Dm2 did not correlate with mRNA levels in similarly treated Δsmg eggs (not shown). Dm3 and Dm4 correlated with mRNA levels changing between wild-type and Δkep1 flies (GEO accession GSE6086), suggesting that Dm3 and Dm4 may reflect the specificity of Kep1, an RNA-binding protein. (C) Dm5 and Dm6 were detected from microarray data measuring mRNA association with ribosomes in early drosophila development (Qin et al, 2007). Triangles represent increasing density of sucrose gradient fractions, corresponding to increasing numbers of ribosomes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2683727&req=5

f4: Putative Drosophila structural cis-regulatory elements. (A) The structural logos of the six putative Drosophila SCREs. (B) Dm1, Dm2, Dm3, and Dm4 were detected using mRNA expression microarray data. Dm1 and Dm2 had strong negative correlations with mRNA levels over early Drosophila development. Dm1 and Dm2 did not correlate with mRNA levels in similarly treated Δsmg eggs (not shown). Dm3 and Dm4 correlated with mRNA levels changing between wild-type and Δkep1 flies (GEO accession GSE6086), suggesting that Dm3 and Dm4 may reflect the specificity of Kep1, an RNA-binding protein. (C) Dm5 and Dm6 were detected from microarray data measuring mRNA association with ribosomes in early drosophila development (Qin et al, 2007). Triangles represent increasing density of sucrose gradient fractions, corresponding to increasing numbers of ribosomes.
Mentions: When we applied StructRED to the Drosophila development time courses and other microarray data, we did not specifically try to find the Smaug specificity. In fact, in addition to the Smaug SCREs, we discovered six other putative SCREs, which we have labeled Dm1 through Dm6, that have coherent supporting TFAPs and annotation (Figure 4). First, Dm1 and Dm2 were discovered from the same mRNA expression microarray time course for Drosophila embryogenesis that we discussed for the Smaug SCREs (Tadros et al, 2007). Those transcripts that contain high-affinity instances of Dm1 and Dm2 are expressed at decreasing levels as development proceeds, suggesting that they are involved in destabilizing these transcripts at specific developmental stages. Dm1- and Dm2-containing transcripts have weak enrichments for Gene Ontology categories related to development and protein transport (Supplementary Table 2). Transcripts that contain Dm1 or Dm2 display a bias for expression in the developing female reproductive system. Notably, Dm1 and Dm2 occurrences do not correlate with decreasing expression in Δsmg embryos (data not shown), suggesting that the putative destabilizing effect of Dm1 and Dm2 depends on Smaug. However, Dm1 and Dm2 do not show the translational repression activity that we see with the Smaug SCREs.

Bottom Line: In addition, we discovered six putative SCREs in flies and three in humans.We characterized the SCREs based on their condition-specific regulatory influences, the annotation of the transcripts that contain them, and their locations within transcripts.Overall, we show that modeling functional genomics data in terms of combined RNA structure and sequence motifs is an effective method for discovering the specificities and regulatory roles of RNA-binding proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Center for Genome Sciences, Washington University School of Medicine, St Louis, MO 63108, USA.

ABSTRACT
Gene expression is regulated at each step from chromatin remodeling through translation and degradation. Several known RNA-binding regulatory proteins interact with specific RNA secondary structures in addition to specific nucleotides. To provide a more comprehensive understanding of the regulation of gene expression, we developed an integrative computational approach that leverages functional genomics data and nucleotide sequences to discover RNA secondary structure-defined cis-regulatory elements (SCREs). We applied our structural cis-regulatory element detector (StructRED) to microarray and mRNA sequence data from Saccharomyces cerevisiae, Drosophila melanogaster, and Homo sapiens. We recovered the known specificities of Vts1p in yeast and Smaug in flies. In addition, we discovered six putative SCREs in flies and three in humans. We characterized the SCREs based on their condition-specific regulatory influences, the annotation of the transcripts that contain them, and their locations within transcripts. Overall, we show that modeling functional genomics data in terms of combined RNA structure and sequence motifs is an effective method for discovering the specificities and regulatory roles of RNA-binding proteins.

Show MeSH