Abstract
Modern genetic analysis has shown that most polymorphisms associated with human disease are non-coding. Much of the functional information contained in the non-coding genome consists of cis-regulatory sequences (CRSs) that are required to respond to signal transduction cues that direct cell specific gene expression. It has been hypothesised that many diseases may be due to polymorphisms within CRSs that alter their responses to signal transduction cues. However, identification of CRSs, and the effects of allelic variation on their ability to respond to signal transduction cues, is still at an early stage. In the current review we describe the use of comparative genomics and experimental techniques that allow for the identification of CRSs building on recent advances by the ENCODE consortium. In addition we describe techniques that allow for the analysis of the effects of allelic variation and epigenetic modification on CRS responses to signal transduction cues. Using specific examples we show that the interactions driving these elements are highly complex and the effects of disease associated polymorphisms often subtle. It is clear that gaining an understanding of the functions of CRSs, and how they are affected by SNPs and epigenetic modification, is essential to understanding the genetic basis of human disease and stratification whilst providing novel directions for the development of personalised medicine.
Highlights
The importance of gene regulation cannot be overstated; the evolution of complex multicellular organisms whose cells possess identical genomes, yet exhibit phenotypic and functional diversity, coincides with the evolution of complex gene regulatory systems capable of controlling differential gene expression [1,2]
Comparative genomics [8,9] has been used to demonstrate that conservation of non-coding DNA regions between evolutionarily divergent species is a powerful tool for the prediction of cis-regulatory sequences [10±13] including promoter and enhancer regions, insulators and locus control regions
It is clear from these examples that cis-regulatory sequences (CRSs) play a vital role in evolution, development and human disease, preeminent conjectures concerning the importance of CRSs to evolution and development through gene regulation were made ~40 years ago by Jacob and Monod [40], Britten and Davidson [41,42] and King and Wilson [43]
Summary
The importance of gene regulation cannot be overstated; the evolution of complex multicellular organisms whose cells possess identical genomes, yet exhibit phenotypic and functional diversity, coincides with the evolution of complex gene regulatory systems capable of controlling differential gene expression [1,2]. Multicellular life must have the ability to regulate its transcriptome in response to extracellular signals from the environment, and surrounding cells if it is to develop, adapt and survive To this end eukaryotes have evolved a repertoire of extracellular signals and receptors which activate diverse signal transduction pathways resulting in the regulation of specific genes through recruitment of transcription factor (TF) complexes [3]. Central to this process in many genes is the involvement of cis-regulatory sequences (CRSs); non-coding functional regions of DNA which mediate TF binding and regulate transcription [4]. Regulatory networks; (4) evaluate the effect of endogenous CRS variation in the context of cellular signalling and (5) determine the role that CRS variation plays in human disease and drug response stratification
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