Transcription factor and microRNA motif discovery: The Amadeus platform and a compendium of metazoan target sets

Linhart, Chaim; Halperin, Yonit; Shamir, Ron

doi:10.1101/gr.076117.108

Cited by 168 publications

(214 citation statements)

References 40 publications

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“…Promoter sequences for each RP gene were defined as 600 bases upstream of ATG and truncated when neighboring ORFs overlapped with this region. Cis-regulatory motifs were discovered using the Amadeus software package (28), searching for up to 5 motifs of lengths 8-12 that are significantly enriched as compared with the background set of promoters. Motif targets were identified via the TestMOTIF software program (32) using a three-order Markov background model estimated from the entire set of promoters per genome.…”

Section: Methodsmentioning

confidence: 99%

Gene duplication and the evolution of ribosomal protein gene regulation in yeast

Wapinski

Pfiffner

French

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Coexpression of genes within a functional module can be conserved at great evolutionary distances, whereas the associated regulatory mechanisms can substantially diverge. For example, ribosomal protein (RP) genes are tightly coexpressed in Saccharomyces cerevisiae, but the cis and trans factors associated with them are surprisingly diverged across Ascomycota fungi. Little is known, however, about the functional impact of such changes on actual expression levels or about the selective pressures that affect them. Here, we address this question in the context of the evolution of the regulation of RP gene expression by using a comparative genomics approach together with cross-species functional assays. We show that an activator (Ifh1) and a repressor (Crf1) that control RP gene regulation in normal and stress conditions in S. cerevisiae are derived from the duplication and subsequent specialization of a single ancestral protein. We provide evidence that this regulatory innovation coincides with the duplication of RP genes in a whole-genome duplication (WGD) event and may have been important for tighter control of higher levels of RP transcripts. We find that subsequent loss of the derived repressor led to the loss of a stress-dependent repression of RPs in the fungal pathogen Candida glabrata. Our comparative computational and experimental approach shows how gene duplication can constrain and drive regulatory evolution and provides a general strategy for reconstructing the evolutionary trajectory of gene regulation across species. T he coordinated expression of modules of functionally related genes, such as ribosomal proteins or oxidative phosphorylation enzymes, is often conserved at great evolutionary distances (1). This is consistent with a selective pressure to conserve coordinated transcript levels to maintain functional cellular modules. Recent studies have shown that the regulatory mechanisms controlling conserved modules can diverge, most notably by switching from one regulatory system to another while preserving coregulation (1, 2). However, because previous studies have typically relied on functional expression data from only one or two species, it is unknown whether these changes in regulatory mechanisms affect the expression levels of a module's genes at all or whether both coexpression and expression levels are conserved.A prominent example of a conserved regulatory module is the ribosomal protein (RP) module. Genes encoding RPs are tightly coexpressed in organisms from bacteria to humans (3, 4), consistent with a selective pressure to conserve coordinated transcript levels to maintain a stoichoimetric balance in ribosome assembly. The transcription factors controlling RP gene expression have changed several times since the last common ancestor of the Ascomycota fungi, which span Saccharomyces cerevisiae and Schizosaccharomyces pombe (4-6). These dramatic changes include the loss of the ancestral regulator Tbf1, the emergence of Rap1 as a key activator among the Hemiascomycota (4, 5), as well as the add...

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Section: Methodsmentioning

confidence: 99%

Gene duplication and the evolution of ribosomal protein gene regulation in yeast

Wapinski

Pfiffner

French

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Assuming equal probability for each of the four possible spatial arrangements of two motifs on two strands, the probability for observing k or more occurrences of a specific arrangement out of a total of n occurrences of the motif pair can be computed using the binomial distribution with p = 0.25. The HG and binomial scores are described in detail in Halperin et al (2009) and Linhart et al (2008). SAGE data were obtained from the Genome BC C. elegans Gene Expression Consortium (http://elegans.bcgsc.bc.ca).…”

Section: Computational Analysesmentioning

confidence: 99%

A novel candidate cis-regulatory motif pair in the promoters of germline and oogenesis genes in C. elegans

Linhart

Halperin²,

Darom³

et al. 2011

Genome Res.

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In this study we report on a novel pair of cis-regulatory motifs in promoter sequences of the nematode Caenorhabditis elegans. The motif pair exhibits extraordinary genomic traits: The order and the orientation of the two motifs are highly specific, and the distance between them is almost always one of two frequent distances. In contrast, the sequence between the motifs is variable across occurrences. Thus, the motif pair constitutes a nearly combinatorial sequence configuration. We further show that this module is conserved among, and unique to, the entire Caenorhabditis genus. By analyzing several gene expression data sets, our data suggest that this motif pair may function in germline development, oogenesis, and early embryogenesis. Finally, we verify that the motifs are indeed functional cis-regulatory elements using reporter constructs in transgenic C. elegans.

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“…In Figure 1(b), we compare the performance of the two similarity measures based on the correlation of score profiles using sequences of length 4 10 with three column-based measures using as CEBPB (10) CTCF (125) EP300 (15) EZH2 (14) JUN (10) JUND (10) MAX (11) MYC (22) RAD21 (13) RELA (10) REST (12) TAF1 ( column-wise measures Pearson correlation, Euclidean distance, and the symmetric Kullback-Leibler divergence (Harbison et al, 2004;Linhart et al, 2008), and with Mosta (Pape et al, 2008). We find that Mosta and the two measures based on the correlation of score profiles yield a substantially increased AUC-PR compared to the column-based measures.…”

Section: Benchmarksmentioning

confidence: 99%

Motif clustering with implications for transcription factor interactions

Grau

Große

Posch

et al. 2015

Preprint

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High-throughput data, for instance ChIP-seq data, measure binding of transcription factors (TFs) or other proteins to DNA and have become a widespread data source for de-novo motif discovery. Often, several ChIP-seq data sets study the same TF under different conditions resulting in several, potentially redundant motifs, which demands for identification and clustering of similar motifs. Here, we propose a refined measure of motif similarity based on the correlation between score profiles on de Bruijn sequences. We demonstrate the utility of the proposed measure in benchmark studies on artificial motifs and motifs discovered from ENCODE ChIP-seq data. We use this measure to cluster motifs discovered from 757 different ENCODE ChIP-seq data sets for 166 TFs and RNA-polymerase II and III. Based on this clustering, we derive a TF interaction network that reflects many known TF-TF interactions, but also reveals novel putative interaction partners.

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Transcription factor and microRNA motif discovery: The Amadeus platform and a compendium of metazoan target sets

Cited by 168 publications

References 40 publications

Gene duplication and the evolution of ribosomal protein gene regulation in yeast

Gene duplication and the evolution of ribosomal protein gene regulation in yeast

A novel candidate cis-regulatory motif pair in the promoters of germline and oogenesis genes in C. elegans

Motif clustering with implications for transcription factor interactions

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