Researchers discover how enhancers can activate genes across domains

A new study has shown for the first time that genetic switches known as enhancers can communicate to genes across domain boundaries, with their ability to do this influenced by a molecular motor – cohesin – that folds our genome inside the cell nucleus.

Our genes are controlled by hundreds of thousands of genetic switches, called enhancers, that can activate their target genes across very large genomic distances, sometimes skipping over intervening genes. 

How enhancers achieve this feat, without inadvertently activating other nearby genes, is unclear. 

The three-dimensional folding of our genome into topologically associating domains (TADs) is thought to be important for allowing enhancers to communicate to their target genes across large tracts of DNA. 

In turn, the boundaries of these domains are thought to prevent enhancers acting on inappropriate genes in neighbouring domains. 

However, a study by researchers at the Institute of Genetics and Cancer published in Genes and Development, found that some enhancers can communicate to genes across domain boundaries.

It highlights an enhancer associated with the sonic hedgehog gene (Shh), a key player in mammalian development, which can also activate another gene called Mnx1, located in the adjacent TAD.

The study found that the enhancer’s ability to do this is influenced by the cohesin motor which folds the genome allowing the enhancer to connect with target genes across domain borders.

This study was published in the journal Genes & Development in an article entitled "Bystander activation across a TAD boundary supports a cohesin-dependent transcription cluster model for enhancer function".

This work sheds light on how our genes are regulated to ensure normal development and highlights the challenge of identifying the genes affected by disease-associated enhancer mutations in the non-coding ‘dark’ genome.

Professor Wendy Bickmore Director of the MRC Human Genetics Unit
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