Insulated neighborhood

In mammalian biology, insulated neighborhoods are chromosomal loop structures formed by the physical interaction of two DNA loci bound by the transcription factor CTCF and co-occupied by cohesin. Insulated neighborhoods are thought to be structural and functional units of gene control because their integrity is important for normal gene regulation. Current evidence suggests that these structures form the mechanistic underpinnings of higher-order chromosome structures, including topologically associating domains (TADs). Insulated neighborhoods are functionally important in understanding gene regulation in normal cells and dysregulated gene expression in disease.

Mammalian gene transcription is generally controlled by enhancers. Enhancers can regulate transcription of genes at large distances by looping to physically contact their target genes. This property of enhancers makes it difficult to identify an enhancer’s target gene(s). Insulators, another type of DNA regulatory element, limit an enhancer’s ability to target distal genes when the insulator is located between an enhancer and a potential target. In mammals, insulators are bound by CTCF, but only a minority of CTCF-bound sites function as insulators. CTCF molecules can form homodimers on DNA, which can be co-bound by cohesin; this chromatin loop structure helps constrain the ability of enhancers within the loop to target genes outside the loop. Loops with CTCF and cohesin at the start and end of the loop that restrict enhancer-gene targeting are “insulated neighborhoods.”

Insulated neighborhoods are defined as chromosome loops that are formed by CTCF homodimers, co-bound with cohesin, and containing at least one gene. The CTCF/cohesin-bound regions delimiting an insulated neighborhood are called “anchors.” One study in human Embryonic stem cells identified ~13,000 insulated neighborhoods that, on average, each contained three genes and was about 90kb in size. Two lines of evidence argue that the boundaries of insulated neighborhoods are insulating: 1) the vast majority (~90-97%) of enhancer-gene interactions are contained within insulated neighborhoods and 2) genetic perturbation of CTCF/cohesin-bound insulated neighborhood anchors leads to local gene dysregulation due to novel interactions outside of the neighborhood.

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