Enhancers Are Not Switches – Why We Should Kill a Bad Metaphor

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“All models are wrong, but some models are useful.” So said George E.P. Box. Models are mental shortcuts that simplify complex thoughts/events/etc. There’s nothing really wrong with explaining a complex idea using a model– in fact the quality of your model can show how well you understand the full concept. But “enhancers are genomic switches” is an outdated model that is causing us issues in explaining new findings. I’m not going to just bury this metaphor but also suggest a replacement– “Enhancers are genomic boardrooms.”

First, what is the full definition of an “enhancer?” This is trickier than one would guess for a thing that was discovered decades ago. Protein-coding DNA genes get transcribed (photocopied) into mRNA transcripts. Enhancers are also pieces of DNA that “enhance” the transcription of these protein-coding genes. So if you just have the piece of protein-coding DNA in your experiment, it gets transcribed at level X. If you have the protein-coding gene and the enhancer on a piece of DNA, the protein-coding gene gets transcribed more. This is how we used to think of enhancers.

As genomes evolved from simple, circular bacterial DNA to the linear chromosome structure seen in humans, bits of DNA changed or got re-purposed. We can find substantial similarity between the parts of our genomes that code for proteins and the protein-coding genes from our distant ancestors. This is less true of enhancers– they tend to be less “conserved” across evolution. We know many parts of the human genome have certain characteristics of enhancers, but the DNA letters in their spans are tough to find in mice and bacteria. This may mean that, when and where genes are used/transcribed/expressed is the big difference between us and other animals. Gene use/transcription/expression is controlled by enhancers.

Bacteria have one cell type; humans have hundreds. Enhancers in humans control when and where genes are turned on. This is why many researchers and press releases have said that “enhancers are switches.” They can have the effect of some gene or genes being turned on when the enhancer is active. What an “active enhancer” really means is what leads to the breakdown of the metaphor of “enhancers are switches.”

Enhancers are regions of DNA. They don’t have letters in the right order to code for protein though, and enhancers are often hundreds or thousands of letters away from the pieces of DNA that do. So how do enhancers have anything to do with transcription if they can be so far away? Well, DNA is kind of like an old school phone cord. Sure, it twists in the familiar helix shape, but it also loops like string. This way, enhancers can loop toward the genes whose transcription they control in 3D space. What it does when it gets there is only recently starting to be appreciated.

drawing5

Actually, enhancers are like boardrooms. When a meeting is held in a boardroom, decision-makers congregate, and they have some knowledge of the whole system that’s needed to make a decision. The decision-makers of the cell are proteins that bind to DNA to conclude whether or not a gene should be transcribed.

Some protein-coding genes have the right recipe to make proteins that act as signals. (To get technical for a moment, they’re called “transcription factors.”) These signals can mean something about the state of the cell– I’m attacking virus– or the environment the cell is in– it’s hot out– or even something about the type of cell it is– I’m a nerve cell. Production of a certain protein can be the end result of a signal-processing pathway and usually means that some gene needs to be transcribed. So these signalling proteins, whose very existence means something about the cell, bind to enhancers that are responsible for controlling transcription of certain genes. These enhancers get bound by a bunch of other proteins and loop in 3D space to the start of the protein-coding target gene. In this way, enhancers aggregate signals from several information sources to decide whether or not to transcribe given genes.

1) Information-carrying protein binds enhancer
2) Enhancer loops to some target gene
3) Protein-coding gene is transcribed
4) Protein made from transcribed
[Optional] 5) GOTO 1

Why does the “switch” metaphor suck? Calling enhancers “switches” limits the amount of things we can say about the latest findings, the majority of which have to do with what’s going on at/with enhancers. Sure, the end result can be expression of a certain gene, but the switches familiar to a lay audience usually involve only one input and are geographically close to the thing they’re controlling. Enhancers can be really far away in the genome and accumulate decisions made from several bits of information.

The proteins binding to DNA are the managers of different departments that have come to the enhancer boardroom. They have made the decision about if transcription of some gene is right for their purview. If all the department managers bind to DNA, signifying their intent, then transcription happens. They don’t flip switches– they make decision by combining information from many sources.

Some boardrooms are more important than others and decisions made within them can have broad or focused impact. For instance, the enhancers controlling genes whose proteins specify cell type have huge reach and can influence nearly every other gene in the genome. Or, perhaps the decision is more focused on whether or not a certain protein pump needs to be on to get more of chemical X into a cell. Calling enhancers switches makes them too egalitarian.

If you’ve made it this far and hate me for my proposal, fine. But you should also know that enhancers don’t really “enhance” transcription, and the thought-leaders in this field are considering burying the term itself. More on that maybe some other time.

While they live though, enhancers thus are not switches, but they are boardrooms. QED. RIP, bad metaphor.

Tl;dr: Enhancers are DNA segments that bind protein signals and control whether or not a gene is transcribed. Calling enhancers “switches” totally undersells the important part. Protein signals are section managers that meet in the enhancer boardroom to decide to transcribe.

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One Response to Enhancers Are Not Switches – Why We Should Kill a Bad Metaphor

  1. Pingback: Me vs. “MuTEs”: Enhancing Cancer’s Hallmarks via Mutation | The Snarky Scientist

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