Shortening Pathological Nucleotide Repeats by DNA Methylation Editing to Treat Neurodegenerative Diseases

Half of our genome is made of repetitive DNA sequence, considered as dark matter of the human genome. Short tandem nucleotide repeats, meaning repeat of 2-12 bp nucleotides in a tandem fashion, occupy about 3% of our genome, but expansion of some repeats can lead to more than 50 human diseases.  Many of these diseases are neurodegenerative disorders. The goal of our research is to leverage the power of epigenetic mechanism to control these pathological repeats. We have developed a series of DNA methylation editing tools to enable us to precisely edit the status of targeted DNA sequence in vitro and in vivo. By applying these editing tools, we hope to demonstrate how DNA methylation editing can control the dynamics of these short nucleotide repeats toward to the treatment of neurodegenerative diseases.

X. Shawn Liu, PhD received his BA in Chemistry from Nankai University in China, and then completed his PhD training at Purdue University and Stanford University focusing on the signal transduction mediated by protein kinases and ligand-receptor interactions. As a Damon Runyon Postdoctoral Fellow in Rudolf Jaenisch’s laboratory at Whitehead Institute MIT, Dr. Liu developed a series of epigenome editing tools to systematically investigate the functional significance of epigenetic modifications in neurological disorders. In 2020 he joined the Department of Physiology and Cellular Biophysics at Columbia University as a Joan and Paul Marks, MD ’49 Assistant Professor to start his independent research career. Dr. Liu’s long-term research interest aims to understand the molecular mechanisms underlying normal brain functions and to explore therapeutic opportunities for human diseases. His laboratory combines novel molecular tool development with genetic and genomic approaches to explore the roles of epigenetic mechanisms in normal brain functions and uncover the epigenetic basis of disease to accelerate the development of therapeutics to brain diseases.

Short tandem nucleotide repeat expansion in the human genome has emerged as the newly identified genetic cause for neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington disease (HD). A major challenge to treat these diseases is to manage the gain-of-function toxicity caused by repeat containing RNA and proteins damaging the patient’s neurons. To overcome this challenge, we propose to shorten the expanded repeats by DNA methylation editing as a permanent treatment strategy. This proposal is based on our recent observation that DNA methylation editing resulted in contraction of GGGGCC repeats in ALS/FTD neurons and functional rescues of disease-relevant phenotypes. This editing strategy has the potential to treat many other neurodegenerative disorders caused by nucleotide repeat expansion.

"Our project will explore whether shortening the expanded nucleotide repeats by DNA methylation editing can prevent or ameliorate the progress of neurodegenerative diseases caused by repeat expansions."