How super is a super-enhancer?

Over the past few years, a fierce debate has raged on amongst geneticists about whether the enticingly named ‘super-enhancer’, a region of the DNA proposed to have essential functions in controlling how a cell works, actually exists. Last month, a study by a team of scientists in Doug Higgs’ lab at the WIMM finally took apart this question piece by piece – and they found that there is nothing very ‘super’ about a super-enhancer at all. Marieke Oudelaar, a DPhil student in the Higgs and Hughes labs who was involved in the work, explains more.

Our bodies are composed of trillions of cells which each have a specific job: eye cells detect light, muscle cells contract to move our limbs, immune cells kill off invaders, etc. Each of these cells produces a specific set of proteins that are required for its specific job. The instructions for these proteins are encoded in distinct sequences in our DNA called genes.

Because all our cells contain the same DNA (as they are all derived from the same fertilised egg), scientists have long wondered how cells know which part of their DNA to use for the production of their required set of proteins, and thus what determines the identity of a cell.

Only a small part of our DNA (~2%) actually consists of genes that code for proteins. But the remaining part is not just ‘junk’, as was initially thought by some. It also contains regulatory DNA sequences that control the activity of our genes. An important class amongst these sequences are enhancers, which function as switches to control whether a given gene is active (e.g. producing protein) or not.

Because these switches are only functional in certain cell types at certain times, they are thought to be crucial for the establishment of cell identity. It is therefore also not surprising that mutations in these switches have been observed in various diseases such as cancer, Alzheimer’s disease and diabetes.

Many genes that are particularly important for determining cell identity are controlled by multiple switches that cluster together, making these regions critical in ensuring the cell is able to function normally. In 2013 it was proposed that these clustered switches form a distinct class of regulatory DNA sequences with higher-order properties, for which the term ‘super-enhancer’ was introduced. Cell identity was suggested to be determined by the activity of a small set of these super-switches.

But the concept of super-enhancers was met with scepticism by other scientists in the field. Many thought that there was little evidence that these regions actually represented a novel class of regulatory DNA sequences, and it was suggested that the observed potent effects could just as well simply be the sum of the independent effects of the individual switches in the clusters.

To resolve this debate, a team of scientists in Doug Higgs’ lab at the WIMM undertook a detailed study of the properties of one of the strongest proposed ‘super-enhancers’ that is essential for the function of red blood cells, which carry oxygen around your body.

To work out whether this cluster of five individual enhancers forms an actual super-enhancer with properties that are more than the sum of the contributions of the individual components, they generated a series of genetically modified mice in which each of the five switches was deleted individually and in informative combinations. By studying the effects of these deletions on gene activity and the function of the red blood cells, they demonstrated that the individual elements act independently and in an additive fashion. The potent effect of this ‘super-enhancer’ turns out to be nothing more than the combined effect of the individual enhancers, and so perhaps isn’t so ‘super’ after all.