Discovering regulatory motifs in the <i>Plasmodium</i> genome using comparative genomics

Wu, Jie; Sieglaff, Douglas H.; Gervin, Joshua; Xie, Xiaohui

doi:10.1093/bioinformatics/btn348

Cited by 31 publications

(25 citation statements)

References 25 publications

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“…Recently, de Silva et al (12) established the functionality of two members of the ApiAP2 family of putative transcription factors and their binding motifs (2). Bioinformatic approaches have predicted many conserved motifs associated with coregulation (65,72,75), but in few resulting cases have physiological relevance to regulation, sufficiency of the motif alone, and biochemical function all been demonstrated jointly.With limited direct evidence that the observed steady-state patterns of most Plasmodium genes are driven by promoterbased transcriptional regulation during the IDC, complementary mechanisms of widespread posttranscriptional regulation have received increasing attention. RNA-binding proteins were predicted to be abundant in P. falciparum (8), a temporal…”

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Patterns of Gene-Specific and Total Transcriptional Activity during thePlasmodium falciparumIntraerythrocytic Developmental Cycle

et al. 2009

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The relationships among gene regulatory mechanisms in the malaria parasite Plasmodium falciparum throughout its asexual intraerythrocytic developmental cycle (IDC) remain poorly understood. To investigate the level and nature of transcriptional activity and its role in controlling gene expression during the IDC, we performed nuclear run-on on whole-transcriptome samples from time points throughout the IDC and found a peak in RNA polymerase II-dependent transcriptional activity related to both the number of nuclei per parasite and variable transcriptional activity per nucleus over time. These differential total transcriptional activity levels allowed the calculation of the absolute transcriptional activities of individual genes from gene-specific nuclear run-on hybridization data. For half of the genes analyzed, sense-strand transcriptional activity peaked at the same time point as total activity. The antisense strands of several genes were substantially transcribed. Comparison of the transcriptional activity of the sense strand of each gene to its steady-state RNA abundance across the time points assayed revealed both correlations and discrepancies, implying transcriptional and posttranscriptional regulation, respectively. Our results demonstrate that such comparisons can effectively indicate gene regulatory mechanisms in P. falciparum and suggest that genes with diverse transcriptional activity levels and patterns combine to produce total transcriptional activity levels tied to parasite development during the IDC.Plasmodium falciparum, the most deadly human malaria parasite, undergoes many developmental changes and thrives in both human and mosquito hosts. Since the genome sequence of P. falciparum became available (17), microarray studies of its intraerythrocytic developmental cycle (IDC) (3, 37) and other asexual and bloodborne stages (34) have demonstrated that differential gene expression is integral to the parasite's development. The stage specificity of steady-state RNA expression supports previous observations that the morphological changes of the IDC correspond to many less-apparent changes in physiology, such as protein and nucleic acid metabolism (10, 19) and sensitivity to small molecules (14, 22, 61). The Plasmodium repertoire of gene regulatory mechanisms is comparable to those of other eukaryotes (7, 23), implying that stage-specific gene expression may be regulated at many levels, including chromatin structure, transcriptional activation, and posttranscriptional modulation of translation and stability (11,39,41,59). However, the relationship between such mechanisms during the IDC, specifically whether regulation of primary transcriptional activity determines the steadystate RNA level, remains uncertain for the vast majority of genes.P. falciparum's steady-state expression patterns during the IDC have been hypothesized to result from cis-acting regulatory DNA sequences (e.g., promoters and enhancers), given its canonical basal transcriptional machinery (4,5,55). Numerous studies of individual puta...

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Patterns of Gene-Specific and Total Transcriptional Activity during thePlasmodium falciparumIntraerythrocytic Developmental Cycle

et al. 2009

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“…The long divergence times and variability make difficult CRE discovery and analyses that require regional sequence alignments. An algorithm, motif discovery using orthologous sequences (MDOS) was developed that does not require anchoring of orthologous sequences (10). MDOS assigns a conservation z-score, which is a statistical measure of how often a specific, short-DNA sequence (7-9 nucleotides in our study) is conserved in the putative control DNA of orthologous genes.…”

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Comparative genomics allows the discovery of cis -regulatory elements in mosquitoes

Sieglaff

Dunn

Xie

et al. 2009

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

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The discovery and mapping of cis-regulatory elements is important for understanding regulation of gene transcription in mosquito vectors of human diseases. Genome sequence data are available for 3 species, Aedes aegypti, Anopheles gambiae, and Culex quinquefasciatus (Diptera: Culicidae), representing 2 subfamilies (Culicinae and Anophelinae) that are estimated to have diverged 145 to 200 million years ago. Comparative genomics tools were used to screen genomic DNA fragments located in the 5 -end flanking regions of orthologous genes. These analyses resulted in the identification of 137 sequences, designated ''mosquito motifs,'' 7 to 9 nucleotides in length, representing 18 families of putative cis-regulatory elements conserved significantly among the 3 species when compared to the fruit fly, Drosophila melanogaster. Forty-one of the motifs were implicated previously in experiments as sites for binding transcription factors or functioning in the regulation of mosquito gene expression. Further analyses revealed associations between specific motifs and expression profiles, particularly in those genes that show increased or decreased mRNA abundance in females following a blood meal, and those accumulating transcription products exclusively or preferentially in the midgut, fat bodies, or ovaries. These results validate the methodology and support a relationship between the discovered motifs and the conservation of hematophagy in mosquitoes.gene expression ͉ hematophagy ͉ Aedes ͉ Anopheles ͉ Culex

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“…The best scoring one (HWKTTTTTNGT, see Figure 11a) is partially included in a 47 bp motif previously identified in the 3'UTR of nine translationally repressed transcripts [37], and is very similar to a motif (TYTTTTNGT) identified in the downstream region of some P. falciparum genes by comparative genomics with P. yoelii and P. knowlesi [30]. To the best of our knowledge, the second best scoring motif (AAAAAAAAAAAV, Figure 11b) does not resemble any other motif already described in the literature.…”

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Computational discovery of regulatory elements in a continuous expression space

et al. 2012

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Approaches for regulatory element discovery from gene expression data usually rely on clustering algorithms to partition the data into clusters of co-expressed genes. Gene regulatory sequences are then mined to find overrepresented motifs in each cluster. However, this ad hoc partition rarely fits the biological reality. We propose a novel method called RED2 that avoids data clustering by estimating motif densities locally around each gene. We show that RED2 detects numerous motifs not detected by clustering-based approaches, and that most of these correspond to characterized motifs. RED2 can be accessed online through a user-friendly interface.

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Discovering regulatory motifs in the Plasmodium genome using comparative genomics

Abstract: The new algorithm, named motif discovery using orthologous sequences (MDOS), is available at http://www.ics.uci.edu/ approximately xhx/project/mdos/.

Cited by 31 publications

References 25 publications

Patterns of Gene-Specific and Total Transcriptional Activity during thePlasmodium falciparumIntraerythrocytic Developmental Cycle

Patterns of Gene-Specific and Total Transcriptional Activity during thePlasmodium falciparumIntraerythrocytic Developmental Cycle

Comparative genomics allows the discovery of cis -regulatory elements in mosquitoes

Computational discovery of regulatory elements in a continuous expression space

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