The three-dimensional folding of DNA is the final context that allows for gene transcription to initiate. The folding of DNA into higher order structures is not a random event, and it has long been thought to affect gene transcription. At the nuclear level, chromosomes occupy specific nuclear territories (reviewed by Cremer and Cremer ). Chromatin interactions within and between broad zones of chromosomes lead to nuclear compartments where active genes tend to co-locate, near the center of the nucleus, and inactive genes cluster near the nuclear periphery. This indicates a strong correlation, though not necessarily causation, between nuclear positioning and gene activity (reviewed by Geyer et al. ). At the finest scale, precise DNA folding or “looping” interactions between gene promoters and their distal regulatory elements can be found. DNA looping (level 3) is guided by long-range interactions between DNA sequence elements (level 1), which can be mediated by interacting context creators (level 2). An illustration of the interplay between multiple levels of regulation that leads to a context for gene expression can be found in the regulation of the HOXA locus. Here, chromosomal looping brings the non-coding RNA HOTTIP in close proximity to HOXA genes. HOTTIP recruits the histone 3 lysine 4 modifying complex MLL by binding to WDR5, targeting this complex to the HOXA locus. As a result, HOTTIP controls HOXA gene expression by bridging higher-order chromosomal looping and chromatin modifications . This exemplifies how context provides an environment for communication between regulatory elements in three-dimensional space, leading to either activation or repression of gene transcription.