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.

In this study, we have investigated a possible mechanism that enables CB₁/M₃ receptor cross-talk, using SH-SY5Y cells as a model system. Our results show that M₃ receptor activation initiates signaling that rapidly upregulates the CNR1 gene, resulting in a greatly potentiated CB₁ receptor response to agonists. Calcium homeostasis plays an essential intermediary role in this functional CB₁/M₃ receptor cross-talk. We show that M₃ receptor-triggered calcium release greatly increases CB₁ receptor expression via both transcriptional and translational activity, by enhancing CNR1 promoter activity. The co-expression of M₃ and CB₁ receptors in brain areas such as the nucleus accumbens and amygdala support the hypothesis that the altered synaptic plasticity observed after exposure to cannabinoids involves cross-talk with the M₃ receptor subtype. In this context, M₃ receptors and their interaction with the cannabinoid system at the transcriptional level represent a potential pharmacogenomic target not only for the develop of new drugs for addressing addiction and tolerance. but also to understand the mechanisms underpinning response stratification to cannabinoids.