Columbia University Vagelos College of Physicians and Surgeons is investigating the role of repetitive DNA sequences, often called “junk DNA,” in brain disorders. Xiao Shawn Liu, PhD, an assistant professor at the college, is focusing on short tandem repeats (STRs), which are brief sequences of DNA repeated multiple times in a row.
“For a long time, people thought that this was just ‘junk DNA’—byproducts that accumulated during the evolution of the human genome,” Liu said. He added that while some repetitive sequences play important roles in gene regulation, others may negatively impact health.
Liu’s research centers on how expansions of STRs can contribute to neurological diseases. “For reasons we don’t understand, STRs sometimes expand, adding more copies to the sequence,” he explained. “Though some of these expansions are harmless, others can cause significant problems, particularly in developing or aging neurons.” Expanded STRs have been linked to around 50 neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington’s disease.
Liu has developed CRISPR-based tools for editing the epigenome—the chemical compounds and proteins attached to DNA that regulate its activity. These methods allow precise editing of methyl groups, which can turn genes on or off. According to Liu: “Naturally, when you make a new tool, you want to see what it can do. After developing our DNA methylation editing tools, we were curious to see if they could be used to edit expanded STRs.”
Tests using motor neurons derived from ALS patients showed that editing DNA methylation reduced the number of repeats within STRs, eliminated toxic molecules responsible for neuronal damage, and restored neuron function. This suggests a possible new approach for treating brain diseases.
Liu recently received a MIND (Maximizing Innovation in Neuroscience Discovery) Prize from Pershing Square Philanthropies—a three-year grant totaling $750,000—to further investigate how methylation editing reduces repeat numbers in ALS-related genes and apply this strategy to other neurodegenerative disease models.
In addition to ALS research, Liu’s tools have shown potential in addressing fragile X syndrome by removing methyl groups near silenced genes and reactivating them in affected neurons.
“We’re just beginning to understand these parts of our DNA,” Liu said. “Some of these copies may well be leftover bits of genetic code, but some clearly have important functions, and others are potentially dangerous. There’s a lot we need to sort out.”
