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

• Published in: Current opinion in genetics & development 2024-08, Vol.87, p.102234, Article 102234
• Main Authors: Czapiewski, Rafal, Schirmer, Eric C
• Format: Article
• Language: English
• ISSN: 0959-437X; 1879-0380; 1879-0380
• DOI: 10.1016/j.gde.2024.102234

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. ●The nuclear envelope (NE) contributes to 3D genome organization regulatory control.●NE control of their localization affects the function of genes, enhancers, and miRNA.●Enhancers can be directly or indirectly controlled NE tethering.●Phase separation has many new links to the NE in NUPs and NETs.●Many NE-regulated functions are highly tissue/cell type specific.