Combinatorial binding predicts spatio-temporal cis-regulatory activity

Zinzen, Robert P.; Girardot, Charles; Gagneur, Julien; Braun, Martina; Furlong, Eileen E. M.

doi:10.1038/nature08531

Cited by 378 publications

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“…1A; Sandmann et al 2007;Zinzen et al 2009;Wilczynski and Furlong 2010). For example, out of 1620 Twist-binding sites at 2-4 hpf, 770 (47%) were specific for this time point (from now on called 'early ' binding sites).…”

Section: In Vivo Binding Is Context-dependentmentioning

confidence: 99%

“…We also show that knowledge about cis-regulatory motif requirements in D. melanogaster allows the correct prediction of Twist binding across different Drosophila species, independently of the overall sequence conservation. Finally, we show that combinations of cis-regulatory motifs around in vivo binding sites are predictive of context-specific binding for other TFs and cofactors and the contextspecific distribution of histone modifications in Drosophila (Zinzen et al 2009), C. elegans (Zhong et al 2010), mouse (Visel et al 2009;Lin et al 2010), and human (Verzi et al 2010;Palii et al 2011;RadaIglesias et al 2011), for which time-, celltype-, or tissue-specific chromatin immunoprecipitation (ChIP) data sets were available. (Zinzen et al 2009) differ between developmental time points (2-4, 4-6, and 6-8 hpf ).…”

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confidence: 99%

“…Here, we elucidate sequence determinants of context-specific TF binding in Drosophila, C. elegans, mouse, and human (Table 1; MacArthur et al 2009;Visel et al 2009;Zinzen et al 2009;Lin et al 2010;Verzi et al 2010;Zhong et al 2010;Palii et al 2011;Rada-Iglesias et al 2011), focusing mainly on a time course of Twist binding in the early Drosophila embryo (Zinzen et al 2009). We show that context-specific Twist binding is explained by the presence of specific motif combinations for other TFs.…”

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confidence: 99%

“…However, the relation between TF motifs and in vivo binding sites is far from simple: First, there is typically a large discrepancy between the number of motif occurrences and in vivo binding sites and most of even the highestscoring motif occurrences are not bound. For example, during Drosophila embryogenesis, the mesodermal TF Twist binds to only about a thousand of the roughly 1 million Twist motifs in the genome (Sandmann et al 2007;Zeitlinger et al 2007;Zinzen et al 2009). Second, in vivo TF binding appears to be highly contextspecific, and the same TF typically binds to different genomic binding sites in different conditions (e.g., Zeitlinger et al 2003;Buck and Lieb 2006;Sandmann et al 2007;Zinzen et al 2009;Wilczynski and Furlong 2010;Palii et al 2011).…”

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confidence: 99%

“…For example, during Drosophila embryogenesis, the mesodermal TF Twist binds to only about a thousand of the roughly 1 million Twist motifs in the genome (Sandmann et al 2007;Zeitlinger et al 2007;Zinzen et al 2009). Second, in vivo TF binding appears to be highly contextspecific, and the same TF typically binds to different genomic binding sites in different conditions (e.g., Zeitlinger et al 2003;Buck and Lieb 2006;Sandmann et al 2007;Zinzen et al 2009;Wilczynski and Furlong 2010;Palii et al 2011). Twist-binding sites, for example, change dynamically between different time points during embryonic mesoderm development (2-8 h post-fertilization, hpf), which cannot be attributed to changes of Twist activity (e.g., by alternative splicing or post-translational modification) or concentration (Sandmann et al 2007;Zinzen et al 2009;Wilczynski and Furlong 2010; see also Fig.…”

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Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

et al. 2012

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The regulation of gene expression is mediated at the transcriptional level by enhancer regions that are bound by sequence-specific transcription factors (TFs). Recent studies have shown that the in vivo binding sites of single TFs differ between developmental or cellular contexts. How this context-specific binding is encoded in the cis-regulatory DNA sequence has, however, remained unclear. We computationally dissect context-specific TF binding sites in Drosophila, Caenorhabditis elegans, mouse, and human and find distinct combinations of sequence motifs for partner factors, which are predictive and reveal specific motif requirements of individual binding sites. We predict that TF binding in the early Drosophila embryo depends on motifs for the early zygotic TFs Vielfaltig (also known as Zelda) and Tramtrack. We validate experimentally that the activity of Twist-bound enhancers and Twist binding itself depend on Vielfaltig motifs, suggesting that Vielfaltig is more generally important for early transcription. Our finding that the motif content can predict contextspecific binding and that the predictions work across different Drosophila species suggests that characteristic motif combinations are shared between sites, revealing context-specific motif codes (cis-regulatory signatures), which appear to be conserved during evolution. Taken together, this study establishes a novel approach to derive predictive cis-regulatory motif requirements for individual TF binding sites and enhancers. Importantly, the method is generally applicable across different cell types and organisms to elucidate cis-regulatory sequence determinants and the corresponding trans-acting factors from the increasing number of tissue-and cell-type-specific TF binding studies.

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Section: In Vivo Binding Is Context-dependentmentioning

confidence: 99%

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Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

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Expanding the mesodermal transcriptional network by genome‐wide identification of Zinc finger homeodomain 1 (Zfh1) targets

Kuo

Kao

et al. 2019

FEBS Letters

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The Drosophila transcription factor (TF) Zfh1 has distinct roles compared to the cell lineage‐determining TFs in almost all mesoderm‐derived tissues. Here, we link Zfh1 to the well‐characterized mesodermal transcriptional network. We identify five enhancers integrating upstream regulatory inputs from mesodermal TFs and directing zfh1 expression in mesoderm. Most downstream Zfh1‐target genes are co‐bound by mesodermal TFs, suggesting that Zfh1 and mesodermal TFs act on the same sets of co‐regulated genes during the development of certain mesodermal tissues. Furthermore, we demonstrate that Zfh1 is critical for the expression of a hemocyte marker gene peroxidasin and helps restrict the activity of a hemocyte‐specific enhancer of serpent to hemocyte‐deriving head mesoderm, suggesting a potential role of Zfh1 in hemocyte development.

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Clinical and Phenotypic Relevance of cis ‐Acting Regulatory Polymorphisms

Liebert

Jones

Swallow

2014

Encyclopedia of Life Sciences

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Genetic variants that regulate the expression level of a transcript are known as expression quantitative trait loci (eQTLs) or regulatory single nucleotide polymorphisms. Cis ‐variants are those that only act on a target gene (or genes) on the same chromosomal homologue. They cause additive differences in gene expression that are tightly associated with the three genotypes of the regulatory eQTL, and cause allelic expression imbalance in heterozygous samples. Unlike trans ‐variants, which can act on many genes located at a distance, cis ‐acting variants are less likely to have all‐or‐none effects if inactivated, and these may be tissue specific and thus less severe. Such cis ‐variants are found occasionally in Mendelian disease and now increasingly implicated in polygenic disorders. The interactions of these regulatory variations with other genetic and also environmental factors are likely to account for some of the complexity of multifactorial diseases. Key Concepts: Regulatory polymorphisms, otherwise known as eQTLs (expression quantitative trait loci), are DNA sequence variations that alter the level of expression of particular transcripts. Cis ‐eQTLs are cis ‐acting polymorphisms that cause variation in the expression of a nearby gene or genes on the same chromosomal homologue. In heterozygous individuals there is a difference in the level of expression from each of the pair of genes transcribed from the two chromosomal homologues. This difference in expression in heterozygous individuals can be observed as allelic expression imbalance (AEI) if there are also allelic sequence differences in the transcript. Such AEI is distinguishable from imprinting in that unlike the case of imprinting the higher expressing transcript can come from either the mother or the father. Cis ‐acting polymorphisms can affect expression in a tissue‐specific and developmentally specific manner. They are strong candidates for positive selection and evolutionary adaptation but such variants might be maladaptive in different environments. Cis ‐acting regulatory sequence changes have been identified as a class of rare mutations in Mendelian disorders, and more common variants are increasingly implicated as causal polymorphisms involved in multifactorial diseases.

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Combinatorial binding predicts spatio-temporal cis-regulatory activity

Cited by 378 publications

References 56 publications

Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

Uncovering cis-regulatory sequence requirements for context-specific transcription factor binding

Expanding the mesodermal transcriptional network by genome‐wide identification of Zinc finger homeodomain 1 (Zfh1) targets

Clinical and Phenotypic Relevance of cis ‐Acting Regulatory Polymorphisms

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