Alzheimer’s Junk DNA: Scientists Solve the 98% Mystery
“`html
When people picture DNA, they ofen 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 slice of our genetic code. Just around 2% of DNA contains our 20,000-odd genes. The other 98% has long been labelled the non-coding genome, or so-called ‘junk’ DNA. This larger portion includes many of the control switches that determine when genes turn on and how strongly they act.
Researchers from UNSW Sydney have now pinpointed DNA switches that help regulate astrocytes. Astrocytes are brain cells that support neurons, and they are known to be involved in Alzheimer’s disease. Their role extends beyond simple support; they regulate blood flow, maintain the chemical balance of the brain, and even influence synaptic transmission – the communication between neurons. A growing body of evidence suggests that astrocyte dysfunction is a key early event in the development of Alzheimer’s disease, potentially even *before* the formation of amyloid plaques and tau tangles.
In research published on December 18 in Nature Neuroscience, a team from UNSW’s School of Biotechnology & Biomolecular Sciences reported that they tested nearly 1000 possible switches in lab-grown human astrocytes. These switches are strings of DNA called enhancers. Enhancers can sit far from the genes they influence, sometimes separated by hundreds of thousands of DNA letters, which makes them challenging to investigate.
Testing Nearly 1000 Enhancers at Once
To tackle that problem, the researchers combined CRISPRi with single-cell RNA sequencing. CRISPRi is a method that can switch off small stretches of DNA without cutting it. Single-cell RNA sequencing measures gene activity in individual cells.Together, the tools let the team examine the effects of nearly 1000 enhancers in a single large-scale test.
“We used CRISPRi to turn off potential enhancers in the astrocytes to see whether it changed gene expression,” says lead author Dr. Nicole Green. “And if it did, then we knew we’d found a functional enhancer and could then figure out which gene — or genes — it controls. That’s what happened for about 150 of the potential enhancers we tested. And strikingly,a large fraction of these functional enhancers controlled genes involved in astrocyte function and Alzheimer’s disease.”