Enhancer jungles establish robust tissue-specific regulatory control in the human genome.

An increasing number of studies suggest that functionally redundant enhancers safeguard development via buffering gene expression against environmental and genetic perturbations. Here, we identified over-represented clusters of enhancers (enhancer jungles or EJs) in human B lymphoblastoid cells. We found that EJs tend to associate with genes involved in the activation of the immune system response. Although spanning multiple genes, the enhancers within an EJ tend to collaborate with each other on regulating a single gene. The employment of homotypic transcription factor binding sites (TFBSs) in EJ enhancers and heterotypic TFBSs between constituent enhancers within an EJ may safeguard a robust transcriptional output of the target gene. EJ enhancers evolve under a weaker selective pressure compared to regular enhancers (REs), and approximately 35% of EJs do not have orthologues in the mouse genome. In GM12878, these human-specific EJs appear to regulate genes associated with the adaptive immune system response, while the conserved EJs are associated with innate immunity. Recently acquired human EJs are associated with the higher level of target gene expression compared with conserved EJs, thus facilitating the environmental adaptation of the organism during evolution. In short, the existence of EJs is a common regulatory architecture conferring a robust regulatory control for key lineage genes.