Fig. 4

Altering the 3D genome architecture disrupts gene expression regulation. a, b An enhancer (green triangle) can modulate gene expression by interacting with and delivering transcription factors to its target gene promoter (yellow rectangle) through long-range enhancer–promoter interactions. A causal mutation (red bar) in the enhancer can alter gene expression by modulating the frequency of this interaction. Impairing the frequency of the long-range interaction reduces delivery of transcription factors to the promoter, thus hindering gene expression (a). Enhancing interactions between the enhancer and promoter facilitates gene expression (b). c, d Insulated neighborhoods can regulate gene expression by restricting interactions between active enhancers (green triangle) and target gene promoters (blue rectangle) within an insulated loop boundary. Causal mutations (red bar) that disrupt CTCF anchor motifs can modify (c) or disrupt (d) existing loops, allowing the once-restricted enhancer (green triangle) to now interact with gene promoters (yellow rectangle) outside of the original insulated neighborhood