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A gene regulatory network directed by zebrafish No tail accounts for its roles in mesoderm formation.

ABSTRACT: Using chromatin immunoprecipitation combined with genomic microarrays we have identified targets of No tail (Ntl), a zebrafish Brachyury ortholog that plays a central role in mesoderm formation. We show that Ntl regulates a downstream network of other transcription factors and identify an in vivo Ntl binding site that resembles the consensus T-box binding site (TBS) previously identified by in vitro studies. We show that the notochord-expressed gene floating head (flh) is a direct transcriptional target of Ntl and that a combination of TBSs in the flh upstream region are required for Ntl-directed expression. Using our genome-scale data we have assembled a preliminary gene regulatory network that begins to describe mesoderm formation and patterning in the early zebrafish embryo.

SUBMITTER: Morley RH

PROVIDER: S-EPMC2656165 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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A gene regulatory network directed by zebrafish No tail accounts for its roles in mesoderm formation.

Morley Rosalind H RH Lachani Kim K Keefe Damian D Gilchrist Michael J MJ Flicek Paul P Smith James C JC Wardle Fiona C FC

Proceedings of the National Academy of Sciences of the United States of America 20090218 10

Using chromatin immunoprecipitation combined with genomic microarrays we have identified targets of No tail (Ntl), a zebrafish Brachyury ortholog that plays a central role in mesoderm formation. We show that Ntl regulates a downstream network of other transcription factors and identify an in vivo Ntl binding site that resembles the consensus T-box binding site (TBS) previously identified by in vitro studies. We show that the notochord-expressed gene floating head (flh) is a direct transcriptiona ...[more]

PMID: 19225104

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Project description:Using chromatin immunoprecipitation combined with microarrays we have identified targets of No tail (Ntl), a zebrafish Brachyury ortholog that plays a central role in mesoderm formation. We show that Ntl regulates a downstream network of other transcription factors and identify an in vivo Ntl binding site that resembles the consensus T-box binding site (TBS) previously identified by in vitro studies. We show floating head (flh) is a direct transcriptional target of Ntl in the notochord and that TBS in the flh upstream region are required for Ntl directed expression. Using this genome-scale data we have assembled a Gene Regulatory Network that describes mesoderm formation and patterning in the early zebrafish embryo and which predicts a role for Ntl in somite segmentation. Keywords: ChIP-chip Genomic array design. Microarrays were designed as described below and manufactured by Agilent Technologies (www.agilent.com). We have previously described the ChIP-chip technique in zebrafish and the design of promoter microarrays which cover a 2kb region around the transcription start sites (TSSs) of 11,512 zebrafish genes based on Zv4 (Wardle et al, 2006. Genome Biology 7:R71). In order to capture additional regulatory information further from the basal promoter region we also designed an expanded set of 60mer probes that cover 9kb upstream and 3kb downstream of the TSS of these genes using the same parameters as for the 2kb microarrays. We also incorporated several sets of control probes, both positive and negative. On each array there are 753 negative probes designed against zebrafish gene desert regions and Arabidopsis thaliana genes. In addition we included duplicates of promoter probes for several genes that we anticipated may be bound by factors of interest for this and other studies (wnt11, flh, vent, msgn1, myod, fgf8, pcdh8) and these probes are arrayed on both slides slide. We also included in this design 502 intensity control probes. Finally there are 2,256 controls added by Agilent. The final design contained 378,002 probes, including 365,537 experimental probes divided between nine microarray slides: slides 1-8 contained 40,616 experimental probes and slide 9 contained 40, 609. Further information on design and manufacture of the microarrays can be found on the Agilent Technologies website (www.agilent.com).

Project description:BackgroundAccurately identifying gene regulatory network is an important task in understanding in vivo biological activities. The inference of such networks is often accomplished through the use of gene expression data. Many methods have been developed to evaluate gene expression dependencies between transcription factor and its target genes, and some methods also eliminate transitive interactions. The regulatory (or edge) direction is undetermined if the target gene is also a transcription factor. Some methods predict the regulatory directions in the gene regulatory networks by locating the eQTL single nucleotide polymorphism, or by observing the gene expression changes when knocking out/down the candidate transcript factors; regrettably, these additional data are usually unavailable, especially for the samples deriving from human tissues.ResultsIn this study, we propose the Context Based Dependency Network (CBDN), a method that is able to infer gene regulatory networks with the regulatory directions from gene expression data only. To determine the regulatory direction, CBDN computes the influence of source to target by evaluating the magnitude changes of expression dependencies between the target gene and the others with conditioning on the source gene. CBDN extends the data processing inequality by involving the dependency direction to distinguish between direct and transitive relationship between genes. We also define two types of important regulators which can influence a majority of the genes in the network directly or indirectly. CBDN can detect both of these two types of important regulators by averaging the influence functions of candidate regulator to the other genes. In our experiments with simulated and real data, even with the regulatory direction taken into account, CBDN outperforms the state-of-the-art approaches for inferring gene regulatory network. CBDN identifies the important regulators in the predicted network: 1. TYROBP influences a batch of genes that are related to Alzheimer's disease; 2. ZNF329 and RB1 significantly regulate those 'mesenchymal' gene expression signature genes for brain tumors.ConclusionBy merely leveraging gene expression data, CBDN can efficiently infer the existence of gene-gene interactions as well as their regulatory directions. The constructed networks are helpful in the identification of important regulators for complex diseases.

Dataset Information

A gene regulatory network directed by zebrafish No tail accounts for its roles in mesoderm formation.

Publications

A gene regulatory network directed by zebrafish No tail accounts for its roles in mesoderm formation.

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