Conserved Motifs and Prediction of Regulatory Modules inCaenorhabditis elegans

Guoyan Zhao,Nnamdi Ihuegbu,Larry Schriefer,Gary D Stormo,Mo Lee,Ting Wang

doi:10.1534/g3.111.001081

Guoyan Zhao, Nnamdi Ihuegbu + Show 4 more

Open Access

https://doi.org/10.1534/g3.111.001081

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Abstract

Transcriptional regulation, a primary mechanism for controlling the development of multicellular organisms, is carried out by transcription factors (TFs) that recognize and bind to their cognate binding sites. In Caenorhabditis elegans, our knowledge of which genes are regulated by which TFs, through binding to specific sites, is still very limited. To expand our knowledge about the C. elegans regulatory network, we performed a comprehensive analysis of the C. elegans, Caenorhabditis briggsae, and Caenorhabditis remanei genomes to identify regulatory elements that are conserved in all genomes. Our analysis identified 4959 elements that are significantly conserved across the genomes and that each occur multiple times within each genome, both hallmarks of functional regulatory sites. Our motifs show significant matches to known core promoter elements, TF binding sites, splice sites, and poly-A signals as well as many putative regulatory sites. Many of the motifs are significantly correlated with various types of experimental data, including gene expression patterns, tissue-specific expression patterns, and binding site location analysis as well as enrichment in specific functional classes of genes. Many can also be significantly associated with specific TFs. Combinations of motif occurrences allow us to predict the location of cis-regulatory modules and we show that many of them significantly overlap experimentally determined enhancers. We provide access to the predicted binding sites, their associated motifs, and the predicted cis-regulatory modules across the whole genome through a web-accessible database and as tracks for genome browsers.

Highlights

Transcriptional regulation, a primary mechanism for controlling the development of multicellular organisms, is carried out by transcription factors (TFs) that recognize and bind to their cognate binding sites
Overview of the conserved motifs identified by PhyloNet To systematically identify conserved elements in C. elegans, we used the genome sequences from C. briggsae and C. remanei
A total of 9356 genes that have both C. briggsae and C. remanei orthologs were used for further analysis

Summary

Introduction

Transcriptional regulation, a primary mechanism for controlling the development of multicellular organisms, is carried out by transcription factors (TFs) that recognize and bind to their cognate binding sites. Authors have shown that TF binding sites tend to cluster together to direct tissue/temporalspecific gene expression (Arnone and Davidson 1997; Kirchhamer et al 1996) These clusters of binding sites that regulate expression are referred to as cis-regulatory modules (CRMs). In this article we performed a genome-wide cis-regulatory element identification using PhyloNet (Wang and Stormo 2005), which systematically identifies phylogenetically conserved motifs that occur multiple times throughout the genome and are likely to define a network of regulatory sites for a given organism. The first step of this approach is similar to that used for cisRED, i.e., identifying segments conserved across multiple species, but it further compares all such conserved regions to each other to identify those associated with multiple genes

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