Healthcare (Commonwealth Union) – Researchers from the University of New South Wales (UNSW Sydney) have identified previously hidden DNA control elements, offering fresh clues into the biological mechanisms behind Alzheimer’s disease.
While DNA is often thought of as a collection of genes, only about 2% of the human genome actually contains the roughly 20,000 genes that code for proteins. The vast majority – the remaining 98% – consists of non-coding DNA, once dismissed as “junk”, but now known to contain crucial regulatory elements that determine when genes are switched on and how active they become.
Researchers from UNSW Sydney have now pinpointed specific DNA switches that regulate the behaviour of astrocytes – support cells in the brain that help neurons function and are increasingly recognised for their involvement in Alzheimer’s disease.
In a study published in Nature Neuroscience, scientists from UNSW’s School of Biotechnology & Biomolecular Sciences explained how they examined almost 1,000 candidate DNA switches, known as enhancers, in human astrocytes grown in laboratory conditions. These enhancers can influence genes located extremely far away along the DNA strand, sometimes separated by hundreds of thousands of genetic letters, which makes them challenging to analyse.
To overcome this, the team combined CRISPR interference (CRISPRi) – a technique that silences specific DNA regions without cutting them – with single-cell RNA sequencing, which tracks gene activity in individual cells. This powerful combination enabled the researchers to assess the roles of nearly 1,000 enhancers simultaneously.
The lead author Dr Nicole Green indicated that by using CRISPRi, they were able to switch off suspected enhancers in astrocytes and observe how gene expression responded.
She further indicated that if it did, then they knew how they found a functional enhancer and could then determine the specific gene – or genes – it has control over. Dr Green then pointed out that it was what occured for about 150 of the possible enhancers they tested and strikingly, a bigger proportion of these functional enhancers had control over the genes implicated in Alzheimer’s disease.
By cutting 1,000 potential candidates down to 150 true switches, scientists have significantly refined where to hunt for genetic signals linked to Alzheimer’s disease in the non-coding genome.
“These findings suggest that similar studies in other brain cell types are needed to highlight the functional enhancers in the vast space of non-coding DNA.”
According to Professor Irina Voineagu, who supervised the study, the findings create a catalogue of DNA regions that can help researchers better interpret data from other genetic investigations.
She indicated that when scientists hunt for genetic variants behind diseases such as hypertension, diabetes, or neurological conditions like Alzheimer’s, they frequently find changes outside genes rather than within them.
Researchers of the study pointed out that these outside regions — known as enhancers — were directly examined in human astrocytes by her team, revealing which ones actually influence crucial 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 — a deeper view into the circuitry of gene control in astrocytes.”
Testing close to a thousand enhancers in the laboratory was an extremely meticulous task, and marks the first time a CRISPR interference screen of this magnitude has been carried out in brain cells. Now that this foundational work is complete, the resulting data can be used to train computational models to distinguish genuine regulatory switches from false leads, potentially cutting years off future experimental research.
Professor Voineagu indicated that this dataset allows computational biologists to rigorously evaluate how accurately their models can predict enhancer activity.
She notes that Google’s DeepMind team is already drawing on the dataset to assess the performance of their latest deep-learning system, AlphaGenome.
Because individual enhancers operate only within particular cell types, targeting them could make it possible to finely tune gene expression in astrocytes while leaving neurons and other brain cells unaffected.
