The Darkness Within

Friday, November 17, 2017

The universe, we are told by astronomers, is made up mostly of dark matter. The normal matter that every one of us has seen or touched here on Earth, in space, or through our telescopes is but a tiny fraction of the whole. Most of the universe— the dark matter — can only be detected through its indirect, gravitational influence on normal matter.

Something similar, it turns out, is happening in our own bodies. Much of our DNA is part of the “dark genome.”

Like dark matter, the dark genome is difficult to detect, and consequently largely unexplored. Also like dark matter, it can only be clearly detected by its influence on the normal genome, on the genes. And unlike the normal genome, it does not contain genes that make its importance clear.

Obviously, any technology that might make the dark genome easier to detect would be a scientific breakthrough.

Recently, UCSF Professor Alexander Marson, his graduate student Dimitri Simeonov and their colleagues published such a breakthrough in Nature. They used their new technology to discover specific regions of the dark genome that are important for the development of autoimmune disease.

Traditionally, to study the dark genome, scientists have had to delete suspected bits of DNA and measure the effect on the amount of the protein made by a nearby gene, one by one.

This is laborious, and requires that the affected gene’s protein be present in the cell, tissue or animal being studied, and receiving a signal from the dark genome at the specific time it is studied.

The bit of DNA being studied may be part of the dark genome, but not in a certain laboratory context at a specific time, leading to a false-negative.

Simeonov and colleagues have found a way to study the dark genome in a fast and context-independent way.

Instead of deleting enhancers, which Simeonov describes as bits of the dark genome that enhance, or increase the production of protein from a nearby gene, the researchers actually turn them on.

“It turns out that if you flip on an enhancer you can now identify the genes that they’re linked to,” Simeonov said. “It’s a fundamentally different approach. Once you flip on the enhancer, you no longer need a specific context to turn it on. You’re providing the signal to that enhancer.”

It's as if to detect the universe’s dark matter more easily, astronomers were able to “turn up” the gravitational attraction to normal matter, causing galaxies to clump and spin in more dramatic and eye-catching ways.

How did Simeonov accomplish the feat? Like many new developments in genetics, he made use of the famous gene-targeting technology called CRISPR. But instead of allowing the CRISPR machinery to cut the DNA, as it normally does, he and his colleagues used a special flavor that “turns up” the activity of the enhancer found at the location in the DNA where the CRISPR is targeted.

Using this precise ability to turn-on enhancers at specific locations, they were able to test many thousands of regions of the genome.

Their hard work paid off, and they uncovered an enhancer that was critical for the control of a particular gene that could eventually lead to new advancements in autoimmune therapies.

“Once you begin to understand what some of these sequences are, you begin to understand how we can engineer them and plop them into different cell types. You potentially can engineer them to fight autoimmunity,” Simeonov said.

In the longer term, he hopes that his new technology can be used to interpret the human genetic diversity that has been discovered by academic scientists, and companies like 23andMe.

In most cases this diversity is not part of the genes themselves, but outside of them, and may be part of the dark genome.

By turning each of these diverse DNA bits “on,” and measuring the effect on genes, he hopes that the functional importance of the human genetic diversity can be appreciated.

Simeonov is ambitious.

“I want to go after the holy grail of genetics, and make functional maps of the whole dark genome,” he said with a gleam in his eye.

But he’s fully aware that this will require the effort of many scientists over decades.

Eventually, he hopes, this will lead to therapies not yet imagined, and a deeper understanding of our human family.