The Regulatory Code for Transcriptional Response Diversity and Its Relation to Genome Structural Properties in A. thaliana

Selbig J (2007) The regulatory code for transcriptional response diversity and its relation to genome structural properties in A. thaliana. PLoS Genet 3(2): e11. doi:10.1371/journal.pgen.0030011 The Regulatory Code for Transcriptional Response Diversity and Its Relation to Genome Structural Properties in A. thaliana Dirk Walther walther@mpimp-golm 0 1 Roman Brunnemann 0 1 Joachim Selbig 0 1 0 Editor: Yoshihide Hayashizaki, RIKEN Genomic Sciences Center , Japan 1 1 Max Planck Institute for Molecular Plant Physiology , Potsdam, Germany , 2 Institute for Biochemistry and Biology, Potsdam University , Potsdam , Germany Regulation of gene expression via specific cis-regulatory promoter elements has evolved in cellular organisms as a major adaptive mechanism to respond to environmental change. Assuming a simple model of transcriptional regulation, genes that are differentially expressed in response to a large number of different external stimuli should harbor more distinct regulatory elements in their upstream regions than do genes that only respond to few environmental challenges. We tested this hypothesis in Arabidopsis thaliana using the compendium of gene expression profiling data available in AtGenExpress and known cis-element motifs mapped to upstream gene promoter regions and studied the relation of the observed breadth of differential gene expression response with several fundamental genome architectural properties. We observed highly significant positive correlations between the density of ciselements in upstream regions and the number of conditions in which a gene was differentially regulated. The correlation was most pronounced in regions immediately upstream of the transcription start sites. Multistimuli response genes were observed to be associated with significantly longer upstream intergenic regions, retain more paralogs in the Arabidopsis genome, are shorter, have fewer introns, and are more likely to contain TATA-box motifs in their promoters. In abiotic stress time series data, multistimuli response genes were found to be overrepresented among early-responding genes. Genes involved in the regulation of transcription, stress response, and signaling processes were observed to possess the greatest regulatory capacity. Our results suggest that greater gene expression regulatory complexity appears to be encoded by an increased density of cis-regulatory elements and provide further evidence for an evolutionary adaptation of the regulatory code at the genomic layout level. Larger intergenic spaces preceding multistimuli response genes may have evolved to allow greater regulatory gene expression potential. - The regulation of gene expression has evolved in cellular organisms as a major adaptive mechanism to respond to environmental changes [15]. How the apparent diversity of responses is encoded in an organisms genome is a central question in understanding transcriptional regulation induced by different environmental and extracellular conditions [6 10]. The induction or repression of particular genes in response to specific environmental challenges is primarily controlled by the recognition and binding of transcriptional regulator proteins (transcription factors) to cis-regulatory elements constituted by short DNA sequence motif sites located in the upstream regions of genes [1113]. Under the simplest scenario of transcriptional regulation, distinct external challenges are matched by specific cognate regulatory sites in upstream regulatory regions of genes that have evolved to respond to the particular perturbation. Genes that are differentially expressed in response to a large number of different external stimuli (multistimuli response genes) are therefore expected to contain more distinct cis-regulatory elements in their upstream regions than are genes that respond to only few environmental cues. There are two plausible strategies of how evolution may have shaped the noncoding, regulatory segments of genomes to encode a greater capacity of downstream genes to respond to a wider range of different stimuli by differential gene expression. A broader response spectrum may have evolved via an increased density of regulatory motifs or via an enlarged size of regulatory intergenic regions to accommodate more elements (or both). In analyzing expression patterns of Caenorhabibditis elegans and Drosophila melanogaster genes in different developmental and tissue differentiation stages, Nelson and coworkers [10] observed that indeed there exists a significant positive correlation between the complexity of a genes expression, that is, to be expressed in a number of different tissues and developmental stages, and the size of its flanking noncoding, intergenic sequence, suggesting that regulatory requirements may have played a significant role in shaping the architecture of genomes. The association of The induction or repression of specific genes has evolved in living organisms as a mechanism to respond to environmental changes. At the molecular level, this process is mediated via molecular switches, so-called regulatory elements, generally located in the genomic region adjacent to the gene they control, the gene promoter. Upon environmental change, specific proteins bind to such regulatory elements, thereby turning on or off the associated genes. As this molecular response is often specific to the external signal, genes that respond to a large number of different external stimuli should harbor more distinct regulatory elements in their promoter regions than should genes responding only to few environmental challenges. In analyzing data for the plant Arabidopsis thaliana, we observed that indeed an increased number of regulatory elements is associated with a broader range of responses. Several other genome structural properties, such as gene size, the occurrence of similar genes in the Arabidopsis genome, and the distance between genes, were also observed to be correlated with a broader breadth of response. The results suggest that greater regulatory complexity appears encoded by an increased density of regulatory elements and provide further evidence for an evolutionary adaptation of the regulatory code at the genomic architectural level. promoters harboring multiple different regulatory sites with differential responses of their downstream genes to varied growth conditions has also been conceptualized by Harbison and coworkers using ChIP-chip yeast data [8]. They distinguished four types of motif arrangements in promoters: single regulatorsassociated with genes of common functions, repetitive motifsallowing graded transcriptional responses, multiple regulatorsallowing responses in diverse conditions, and co-occurring regulatorsfor physically interacting regulators. In this study, we test and quantify the strength of the association of the presence of multiple different regulatory motifs in promoters with the breadth of differential gene expression response to external s (...truncated)