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Different types of cell are defined by which of the genes within the genome are expressed and which are switched off. The activation of a given gene is determined by the presence of protein complexes called transcription factors at regions specific to each gene known as promoters and enhancers. The promoters and enhancers for a particular gene are not necessarily located physically close to each other on the genome, but were thought to be brought into proximity by the DNA forming loops via a poorly understood process.

 

This study in mice suggests the mechanism by which these loops are formed. The researchers found that the proteins Mediator and Cohesin bind simultaneously to both the promoter and enhancer of a gene that is to be activated and form a complex which brings the two separate segments of the genome physically and functionally together, causing the DNA to form a series of characteristic loops for each type of cell.

 

Mediator and Cohesin co-occupy different promoters and enhancers in different cells, creating specific DNA loops associated with the gene expression pattern of each type of cell. This study found that the presence of Mediator and Cohesin at particular promoters and enhancers predicted the looping that would occur, and that disruption of this loop structure caused the cell to lose its normal state and to become a different cell type.

 

One of the study’s authors Richard Young has been quoted as saying that this research reveals “…a surprising new understanding of the control of genes” and could provide “…a fundamental new insight into the underlying causes of several neurological and developmental diseases”.

 

Comment: This study has increased our understanding of how physical changes to the structure of the DNA within a cell alter gene expression, and thus which cell type it will be. It has long been known that the activation of individual genes is dependent upon promoter and enhancer regions associated with that gene, but the means by which these physically separated regions achieved this was poorly understood. Although this study was in mice and not humans, it is expected that a process as fundamental as the control of gene expression will be the same across all vertebrates.

 

A number of developmental disorders in humans, including FG syndrome and schizophrenia, are associated with mutations in the genes that encode Mediator and Cohesin; this study suggests that the underlying cause of these disorders might be changes to the structure of the loops in the DNA that in turn alter patterns of gene expression within certain cells. However, it could be a long time before this knowledge is able to directly inform therapies for specific disorders.