Enhancers on the edge — how the nuclear envelope controls gene regulatory elements

Precise temporal and sequential control of gene expression during development and in response to environmental stimuli requires tight regulation of the physical contact between gene regulatory elements and promoters. Current models describing how the genome folds in 3D space to establish these interactions often ignore the role of the most stable structural nuclear feature — the nuclear envelope. While contributions of 3D folding within/between topologically associated domains (TADs) have been extensively described, mechanical contributions from the nuclear envelope can impact enhancer–promoter interactions both directly and indirectly through influencing intra/inter-TAD interactions. Importantly, these nuclear envelope contributions clearly link this mechanism to development and, when defective, to human disease. Here, we discuss evidence for nuclear envelope regulation of tissue-specific enhancer–promoter pairings, potential mechanisms for this regulation, exciting recent findings that other regulatory elements such as microRNAs and long noncoding RNAs are under nuclear envelope regulation, the possible involvement of condensates, and how disruption of this regulation can lead to disease.