Guoyan Zhao, PhD, assistant professor in the department of neuroscience, has received a U24 grant as a co-investigator from the National Institutes of Health (NIH), as part of the new Impact of Genomic Variation on Function Consortium (IGVF) to investigate how variations in the human genome affect its functions. This $7 million award supports a nationwide collaboration lead by Ting Wang, PhD, the Sanford C. and Karen P. Loewentheil Distinguished Professor of Medicine in the department of genetics, and Feng Yue, PhD, the Duane and Susan Burnham Professor of Molecular Medicine at Northwestern University.
“This is a perfect opportunity for my lab,” says Zhao. “By integrating the huge amount of data generated by the Consortium and our expertise in gene transcriptional regulation, it will help to understand a person’s risk of developing neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.”
The expression of many genes are disturbed in neurodegenerative diseases, yet the mechanisms underlying such alterations are still unknown. Zhao’s lab aims to tackle this question by identifying the changes in the regulatory elements of these altered genes.
Zhao’s team developed a genome-wide model that can predict, in any mammalian genome, the positions of regulatory elements and the transcription factor binding sites in those elements.
“Our model is very special,” Zhao says. “It is purely based on rigorous statistics and genomic sequence instead of training data, whose availability and quality is hard to meet in the mammalian cis-regulatory module prediction field. Prediction made by our model is final in a given organism and can be reliably tested by experimentally defined modules.”
Zhao developed the model in worms during her postdoctoral training in the lab of Gary Stormo, the Joseph Erlanger Professor in the department of genetics and the Center for Genome Sciences and Systems Biology at Washington University School of Medicine. After joining the department of neuroscience in 2018, she has successfully applied the same model on the mammalian system using rats, mice and human genomes.
Seeing the potential of this predictive model in neurodegenerative diseases, her lab is now planning to use it to identify the changes in the regulatory sequences of dysregulated genes by comparing single-cell sequencing data from disease and control conditions. Such work can help identify how these regulatory changes lead to the alteration in gene expression and relate to disease phenotypes. This U24 grant will greatly advance the application of the technique in Zhao’s lab.