When people imagine DNA, they often imagine a set of genes that shape our physical traits, influence behavior, and help keep our cells and organs functioning.
But genes make up only a small portion of our genetic code. Only about 2% of DNA contains our approximately 20,000 genes. The remaining 98% has long been labeled as non-coding genome, or so-called “junk” DNA. This larger portion includes many of the control switches that determine when genes are turned on and how strongly they act.
Astrocytes and DNA switches hidden in the brain
Researchers at UNSW Sydney have identified DNA switches that help regulate astrocytes. Astrocytes are brain cells that support neurons and are known to be involved in Alzheimer’s disease.
In research published on December 18 in Nature NeuroscienceA team from UNSW’s School of Biotechnology and Biomolecular Sciences reported that they tested almost 1,000 potential switches in lab-grown human astrocytes. These switches are strands of DNA called enhancers. Enhancers can be located far from the genes they influence, sometimes separated by hundreds of thousands of DNA letters, making them difficult to investigate.
Testing almost 1000 power-ups at once
To address that problem, the researchers combined CRISPRi with single-cell RNA sequencing. CRISPRi is a method that can disconnect small stretches of DNA without cutting them. Single-cell RNA sequencing measures gene activity in individual cells. Together, the tools allowed the team to examine the effects of nearly 1,000 enhancers in a single large-scale test.
“We used CRISPRi to turn off potential enhancers in astrocytes and see if it changed gene expression,” says lead author Dr. Nicole Green.
“And if it did, then we would know we had found a functional enhancer and then we could determine which gene (or genes) it controls. That’s what happened with about 150 of the potential enhancers we tested. And surprisingly, a large fraction of these functional enhancers controlled genes implicated in Alzheimer’s disease.”
Reducing the list from 1,000 candidates to about 150 confirmed changes greatly reduces the search area in the non-coding genome for genetic clues related to Alzheimer’s disease.
“These findings suggest that similar studies are needed in other brain cell types to highlight functional enhancers in the vast space of non-coding DNA.”
Why “intermediate” DNA is important for many diseases
Professor Irina Voineagu, who supervised the study, says the results also provide a useful reference for interpreting other genetic research. The team’s findings create a catalog of DNA regions that can help explain the results of studies looking for genetic changes linked to disease.
“When researchers look for genetic changes that explain diseases such as hypertension, diabetes, and also psychiatric and neurodegenerative disorders such as Alzheimer’s disease, we often end up with changes not so much within genes but between them,” he says.
His team directly tested those “intermediate” stretches in human astrocytes and showed which enhancers actually control key brain genes.
“We’re not talking about therapies yet. But you can’t develop them unless you first understand the wiring diagram. That’s what this gives us: deeper insight into the genetic control circuits in astrocytes.”
From genetic changes to AI prediction models
Performing nearly a thousand enhancer tests in the laboratory required painstaking effort. The researchers say this is the first time a CRISPRi-boosting test of this size has been performed in brain cells. Now that the preliminary work has been done, the data set can also be used to train computer models to predict which suspected enhancers are actual genetic switches, which could save years of lab work.
“This data set can help computational biologists test how good their prediction models are at predicting enhancer function,” says Professor Voineagu.
He adds that Google’s DeepMind team is already using the data set to benchmark its recent deep learning model called AlphaGenome.
Potential tools for gene therapy and precision medicine
Because many enhancers are active only in specific cell types, targeting them could offer a way to fine-tune gene expression in astrocytes without changing neurons or other brain cells.
“While this is not yet close to being used in the clinic (and there is still a lot of work to be done before these findings can lead to treatments), there is clear precedent,” says Professor Voineagu.
“The first gene-editing drug approved for a blood disease (sickle cell anemia) targets a cell type-specific enhancer.”
Dr. Green says research into enhancers could become an important part of precision medicine.
“This is something we want to look at further: finding out what enhancers we can use to turn genes on or off in a single type of brain cell, and in a very controlled way,” he says.
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