Transcription factor binding to Caenorhabditis elegans first introns reveals lack of redundancy with gene promoters

Juan I Fuxman Bass,Alex M Tamburino,Matthew T Weirauch,Albertha J M Walhout,Nathan Beittel,Akihiro Mori,John S Reece-Hoyes

doi:10.1093/nar/gkt858

Abstract

Gene expression is controlled through the binding of transcription factors (TFs) to regulatory genomic regions. First introns are longer than other introns in multiple eukaryotic species and are under selective constraint. Here we explore the importance of first introns in TF binding in the nematode Caenorhabditis elegans by combining computational predictions and experimentally derived TF–DNA interaction data. We found that first introns of C. elegans genes, particularly those for families enriched in long first introns, are more conserved in length, have more conserved predicted TF interactions and are bound by more TFs than other introns. We detected a significant positive correlation between first intron size and the number of TF interactions obtained from chromatin immunoprecipitation assays or determined by yeast one-hybrid assays. TFs that bind first introns are largely different from those binding promoters, suggesting that the different interactions are complementary rather than redundant. By combining first intron and promoter interactions, we found that genes that share a large fraction of TF interactions are more likely to be co-expressed than when only TF interactions with promoters are considered. Altogether, our data suggest that C. elegans gene regulation may be additive through the combined effects of multiple regulatory regions.

Highlights

The precise expression of genes in space and time plays a central role in development, homeostasis and response to environmental cues
If first introns are important for gene regulation, one would expect that the length of long first introns is more conserved than the length of long non-first introns, as they could potentially contain more TF binding sites (TFBSs) and would be more sensitive to deletions
We investigated the role of C. elegans first introns in gene regulation by combining a systems-level gene-centered protein–DNA interaction (PDI) network, computational predictions and previously published chromatin immunoprecipitation (ChIP) and microarray expression data

Summary

INTRODUCTION

The precise expression of genes in space and time plays a central role in development, homeostasis and response to environmental cues. TF-centered methods such as chromatin immunoprecipitation (ChIP) have been used to identify in vivo binding events for a relatively small number of C. elegans TFs and, usually, only in a single developmental stage [12]. These studies have found that TFs generally bind sequences located within a few hundred nucleotides from the TSS. We show that shared interactions between genes are more predictive of co-expression when both the promoter and the first intron are considered These observations suggest that gene regulation may be additive through multiple regulatory regions

MATERIALS AND METHODS

RESULTS AND DISCUSSION

CONCLUSIONS