When most people think about DNA, they tend to picture genes that determine physical traits, influence behaviour, and keep the body’s cells and organs functioning properly. This familiar image is useful, but it captures only a small slice of what our genetic material actually does. The reality is that genes themselves make up only a minor fraction of the human genome.
In fact, only about 2% of our DNA encodes the roughly 20,000 genes that code for proteins. The remaining 98% belongs to the non-coding genome, long dismissed as “junk” DNA. Scientists now know that much of this DNA is anything but useless, as it contains regulatory elements that act like switches, controlling when genes are activated and how strongly they are expressed.
Researchers from UNSW Sydney have recently identified important DNA switches that regulate astrocytes, specialised brain cells that support neurons and help maintain normal brain function. Astrocytes are increasingly recognised as playing a key role in Alzheimer’s disease, making them an essential target for understanding how genetic regulation contributes to neurodegeneration.
In a study published in Nature Neuroscience, scientists from UNSW’s School of Biotechnology and Biomolecular Sciences examined nearly 1,000 potential switches, known as enhancers, in human astrocytes grown in the laboratory. Enhancers are challenging to study because they can be located far from the genes they regulate, sometimes hundreds of thousands of DNA base pairs apart. To overcome this challenge, the team combined CRISPR interference, which allows sections of DNA to be switched off without cutting them, with single-cell RNA sequencing to measure changes in gene expression.
This approach enabled the researchers to test the function of almost 1,000 enhancers simultaneously. By turning off each candidate enhancer and observing whether gene activity changed, they identified around 150 that functioned as genuine switches. Strikingly, many of these enhancers controlled genes already linked to Alzheimer’s disease, sharply narrowing the regions of the genome that scientists need to examine when searching for genetic risk factors.
Although the findings do not immediately translate into treatments, they provide a crucial foundation for future work. The results offer a detailed map of gene regulation in astrocytes, helping researchers interpret genetic changes found outside of genes themselves. The dataset can also be used to train artificial intelligence tools to predict enhancer function, potentially accelerating future research. In the longer term, the cell-type specificity of enhancers raises the possibility of precisely controlling gene activity in astrocytes, opening new directions for understanding and eventually treating Alzheimer’s disease.
More information: Nicole F. O. Green et al, CRISPRi screening in cultured human astrocytes uncovers distal enhancers controlling genes dysregulated in Alzheimer’s disease, Nature Neuroscience. DOI: 10.1038/s41593-025-02154-3
Journal information: Nature Neuroscience Provided by University of New South Wales
