Transcriptional regulation of eukaryotic genes has classically been viewed as the interaction of elements in the immediate vicinity of the transcription start site (promoters) with upstream elements (enhancers) . Mutations in conserved upstream promoter DNA sequences affect gene expression directly . However, transcriptional regulation is not only determined by DNA sequence but involves additional layers of control that include nucleosome positioning, DNA binding regulatory proteins such as transcription factors, histone modifications and non-coding RNA . Moreover, the development of high throughput chromosome conformation capture techniques has shown that the three-dimensional organization of genes and upstream elements affects transcriptional activity . Here, we present how the combination of these factors can provide a “context” for the regulation of gene expression.