Red Light, Green Light: How Huntington’s Disease Influences Genetic Traffic Lights
Huntington’s disease disrupts genetic "traffic lights," keeping genes green when they should be red. These genetic traffic jams may act to speed brain cell aging and faulty traffic cops fail to stop the chaos. What does this mean for HD?
For Huntington’s disease (HD), a lot of attention goes to the genetic change that causes HD, but new research is shining a light on something else – our epigenome. The word literally means, “above” the “genome”, or above the genetic code. It’s a layer of chemical marks that are added to genes to regulate their activity. Think of the epigenome like a traffic control system for our genes. It’s responsible for deciding when a gene should “go” (get activated) or “stop” (stay quiet). When things go awry, like in HD, that traffic system breaks down.
Genetic Traffic Lights
Imagine a busy intersection – traffic is carefully orchestrated with different colored lights, telling drivers when to stop and when to go. If a signal turns yellow, drivers know that the light is in a transition between letting those cars go, and telling them to stop. These yellow lights are similar to what scientists call “bivalent” marks.
Image credit: Aayush Srivastava
Bivalent genes carry both activating signals (the green light) and repressive signals (the red light) at the same time – like a yellow traffic light. This allows the gene to be ready to turn on quickly when needed, but also to stay off when it’s not. In HD, something goes wrong with these bivalent marks.
Stuck on Green
A surprising finding from this new work, led by Karine Merienne from the University of Strasbourg in France, is that certain genes that are normally “turned off” are staying “on” in the neurons of mice that model HD. The repressive signal (the “red light”) is lost, and the gene becomes more likely to turn on, as if the green light is stuck on. This means that genes which generally stay quiet in brain cells can get activated when they shouldn’t, potentially causing harm to the neuron.
Those stuck green signals are happening in genes that are involved in the early development of the brain. These are genes that help guide how a neuron develops and what kind of neuron it becomes. In a brain without HD, these genes are turned off after the brain develops, but in HD, they seem to be active for longer.
This is similar to what others have recently found, with data suggesting that HD may lead to genetic changes that cause certain brain cells to lose their identity, turning off genes that help define them as unique types of neurons. Until now, we didn’t really know how this might be happening.
“Think of the epigenome like a traffic control system for our genes. It’s responsible for deciding when a gene should “go” (get activated) or “stop” (stay quiet). When things go awry, like in HD, that traffic system breaks down.”
The changes defined by Karine’s team were seen in HD mice, where developmental genes – key players in brain development – were activated in mature neurons. These persistent green traffic signals can make them more accessible for activation, which researchers think could contribute to problems in how neurons function.
“Traffic Cops”
There are special molecular machines in the cell that normally help keep this process in check, two of which are called PRC1 and PRC2. These complexes act like traffic cops, ensuring that genes stay in their proper lanes – some genes should stay off, and others should be on at the right time. PRC1 and PRC2 usually help maintain the “red light” by placing repressive marks on genes, keeping them quiet.
But in HD, it seems like these traffic cops are being overwhelmed. The “red light” is no longer functioning properly, and the genes that should stay quiet (the developmental genes) are getting the green light to turn on. This leads to those genes being active when they shouldn’t be, which could cause the neurons to behave inappropriately.
Researchers have discovered that PRC1 isn’t just losing its repressive marks, but the proteins it relies on to work, seem to also be switched out for less mature versions. Think of it like the traffic cops being replaced with rookie officers who aren’t as good at controlling the traffic. This shift could be a major reason why PRC1 is less effective at stopping the activation of developmental genes seen in the mouse model of HD.
Image credit: wirestock
A Building Traffic Frenzy
One of the most interesting findings is that this disruption doesn’t just happen all at once – it gets worse over time. As the HD mice age, more and more genes begin to be activated inappropriately. It’s as if the “green lights” keep getting stuck on, while the “red lights” continue to fail. The researchers suggest that this progressive breakdown of genetic traffic regulation may cause the neurons to age much faster than they would in a brain without HD. It’s like the cells are “aging” more quickly on a genetic level, which might underlie an earlier decline in their function.
Researchers followed these changes in HD mice and found that over time, the number of genes showing altered epigenetic marks kept increasing. In particular, they saw developmental genes becoming more active as the mice aged. Adding to that, they saw this effect specifically in neurons in the striatum, the part of the brain most affected in HD.
In these cells, the epigenetic marks that normally keep these genes in check were decreasing, while marks that signal activation were increasing. It’s as if the brakes were failing, and the gas pedal was stuck to the floor – such frantic driving would rapidly age most people!
Fixing the Traffic System
“A surprising finding from this new work, led by Karine Merienne from the University of Strasbourg in France, is that certain genes that are normally “turned off” are staying “on” in the neurons of mice that model HD. ”
Understanding how these epigenetic changes contribute to HD opens up exciting possibilities for new treatments in the future. If we can find ways to correct the breakdown in PRC1 and PRC2 function, or restore the balance of the red and green lights at the level of gene regulation, we might be able to slow progression of the disease.
For example, therapies could aim to fix the loss of repressive marks, which would restore the “red light” and keep developmental genes from turning on inappropriately. Other treatments could target the switch in PRC1 proteins, making sure the “mature” traffic cops are in place, keeping the genes under control.
Furthermore, therapies that address the accelerated aging of neurons could help protect the brain from the damage caused by these epigenetic changes. By slowing down the “epigenetic aging” process, we might be able to prevent the brain cells from losing their function too quickly.
Red Lights Ahead?
The discovery of accelerated epigenetic aging in HD gives us a fresh perspective on the disease and offers hope for new treatment strategies. By understanding the role of bivalent promoters, and the malfunctioning PRC1 and PRC2 complexes, researchers could be uncovering how neurons in HD may age prematurely and lose their function.
This new knowledge not only improves our understanding of how HD progresses, but it also opens up the possibility of therapies that could target the underlying epigenetic changes. While there is still much to learn, these findings mark an important step forward in the search for ways to pump the brakes on Huntington’s disease.
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