It is thought that an insulator must reside between the enhancer and promoter to inhibit their subsequent interactions. Insulators therefore determine the set of genes an enhancer can influence. The need for insulators arises where two adjacent genes on a chromosome have very different transcription patterns; it is critical that the inducing or repressing mechanisms of one do not interfere with the neighbouring gene. Insulators have also been found to cluster at the boundaries of topologically associating domains (TADs) and may have a role in partitioning the genome into "chromosome neighborhoods" - genomic regions within which regulation occurs.
Insulator activity is thought to occur primarily through the 3D structure of DNA mediated by proteins including CTCF. Insulated neighborhoods formed by physical interaction between two CTCF-bound DNA loci contain the interactions between enhancers and their target genes.
Mechanism of action
Insulators are likely to function through multiple mechanisms. Many enhancers form DNA loops that put them in close physical proximity to promoter regions during transcriptional activation. Insulators may promote the formation of DNA loops that prevent the promoter-enhancer loops from forming.
Barrier insulators may prevent the spread of heterochromatin from a silenced gene to an actively transcribed gene.
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