DNA motifs in human and mouse proximal promoters predict tissue-specific expression

Abstract

Comprehensive identification of cis-regulatory elements is necessary for accurately reconstructing gene regulatory networks. We studied proximal promoters of human and mouse genes with differential expression across 56 terminally differentiated tissues. Using in silico techniques to discover, evaluate, and model interactions among sequence elements, we systematically identified regulatory modules that distinguish elevated from inhibited expression in the corresponding transcripts. We used these putative regulatory modules to construct a single predictive model for each of the 56 tissues. These predictors distinguish tissue-specific elevated from inhibited expression with statistical significance in 80% of the tissues (45 of 56). The predictors also reveal synergy between cis-regulatory modules and explain large-scale tissuespecific differential expression. For testis and liver, the predictors include computationally predicted motifs. For most other tissues, the predictors reveal synergy between experimentally verified motifs and indicate genes that are regulated by similar tissuespecific machinery. The identification in proximal promoters of cis-regulatory modules with tissue-specific activity lays the groundwork for complete characterization and deciphering of cis-regulatory DNA code in mammalian genomes.cis-regulatory modules ͉ transcription factor binding A major first step toward comprehensively understanding the differential control of gene expression in specific tissues and developmental stages is mapping the functional cis-regulatory modules (CRMs) (1) responsible for transcription regulation. CRMs are autonomous units of transcription programs encoded in DNA (2-4) and are largely composed of transcription factorbinding sites (TFBSs). Identification and categorization of the entire repertoire of TFBSs are among the greatest challenges in systems biology (5-7). Although CRM identification in lower eukaryotes, such as various yeast species, has been progressing rapidly (8, 9), similar efforts in vertebrates have proven to be especially difficult due to the genomic and regulatory complexity of the higher organisms (10). CRMs in vertebrate regulatory regions not only control transcription during the life of individual cells but also must orchestrate cellular communication during tissue differentiation, morphogenesis, and body-part formation (11), as well as maintain specific patterns of transcription in terminally differentiated tissues (12).Recent work to predict expression using cis-regulatory elements includes studies on yeast (6,9,13,14), identification of target genes and binding sites for specific transcription factors (15, 16), and an evaluation of the effect of TFBS quality (17) on target regulation. Bussemaker et al. (13) and Conlon et al. (14) used linear regression to fit the count of predicted cis-regulatory elements (13) or the sum of the likelihood ratios of all potential cis-regulatory elements (14) to expression intensity. Beer and Tavazoie (6) used cis-regulatory elements in promoters to s...

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