If you could look at the entire human genome, you might notice that large sections seem to have been created by a photocopier stuck in the on position.
Fully half of our genome consists of recurring DNA sequences, from short, three-letter strings arranged one right after another to long stretches of hundreds of base pairs scattered over multiple chromosomes.
Xiao Shawn Liu
"For a long time, people thought that this was just 'junk DNA'-byproducts that accumulated during the evolution of the human genome," says Xiao Shawn Liu, PhD, the Joan and Paul Marks, MD '49 Assistant Professor of Physiology and Cellular Biophysics at Columbia University Vagelos College of Physicians and Surgeons.
But scientists have increasingly found that while some repetitive sequences-collectively dubbed the "repeatome"-play important roles in gene regulation, others may have devastating impacts on health.
Short tandem repeats
Liu is focused on a small and little understood category of the repeatome called short tandem repeats, or STRs. STRs are brief sequences of DNA, typically two to 12 base pairs in length, repeated one right after the other (e.g., CAGCAGCAGCAG).
"For reasons we don't understand, STRs sometimes expand, adding more copies to the sequence," Liu says. "Though some of these expansions are harmless, others can cause significant problems, particularly in developing or aging neurons."
Expanded STRs are now thought to play a role in 50 different neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington's disease."We're just beginning to understand these parts of our DNA. 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."
Liu's work hints that it may be possible to prevent STR expansion, or at least counteract their effects, by leveraging the power of epigenetic mechanisms to control these pathological repeats.
Early in his career, Liu made a name for himself creating tools to edit the epigenome-chemical compounds and proteins that attach themselves to the genome and tell it what to do. Liu's CRISPR-based methods allow precise editing of methyl groups, a common epigenetic attachment that turns genes on or off. These tools give researchers new abilities to explore how specific epigenetic attachments contribute to disease and, possibly, develop therapies that counteract deleterious attachments.
"Naturally, when you make a new tool, you want to see what it can do," explains Liu, who joined Columbia University in 2020 after finishing a postdoctoral fellowship at the Whitehead Institute. "After developing our DNA methylation editing tools, we were curious to see if they could be used to edit expanded STRs."
Editing the epigenome
In tests with motor neurons derived from patients with ALS, DNA methylation editing dramatically reduced the number of repeats inside the STR, eliminated toxic molecules that cause neuronal damage, and restored the function of the diseased neurons-potentially paving the way for an entirely new approach to the treatment of brain diseases.
Based on these preliminary studies, Liu recently received a coveted MIND (Maximizing Innovation in Neuroscience Discovery) Prize, awarded by Pershing Square Philanthropies to empower early-to-mid-career investigators to "rethink conventional paradigms around neurodegenerative diseases."
It is still unclear how methylation editing reduces the repeats inside the ALS gene's STR, and Liu is using the three-year, $750,000 prize to further explore the mechanism and apply this strategy to other models of neurodegenerative disease.
In laboratory experiments, Liu's DNA methylation tools have already shown promise in counteracting STRs that cause fragile X syndrome, the most common inherited cause of intellectual disability and autism spectrum traits. By removing methyl groups around the gene that is silenced in fragile X, Liu's editing tools reactivate the gene and restore normal functions to affected neurons.
"We're just beginning to understand these parts of our DNA," says Liu. "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."
