Research

We aim to understand human diseases through computational tools, genomics, and the study of gene regulation. Our main approach is to use genetics to connect gene regulatory variation to and phenotypic variation. Our research interests include:

Mechanisms of gene regulation

Our lab is diving into the gene regulatory cascade, exploring the intricate details of how genetic information flows through it to influence protein expression levels. We examine how DNA variants can substantially alter steps in gene regulation from chromatin to protein. Using this strategy, we can identify regulatory mechanisms that are important players in human disease, and figure out which regulatory mechanisms are more amenable for targeting using existing or novel drugs. As of 2024, we are focused on understanding the connection between alternative splicing, nonsense-mediated decay, and gene expression regulation.

RNA splicing in disease

Our lab is advancing our understanding of the functional links between genetic variants and complex traits. While genetic variant associated with disease risk are often found in non-coding regions of the genome, only about one third of these GWAS hits affect gene expression levels in relevant cells. To uncover the mechanisms behind this discrepancy, we have studied RNA splicing and its association to disease risk, and have applied our findings to a variety of diseases – from neurological disorders like Alzheimer’s and Parkinson’s Disease to many autoimmune diseases such as Rheumatoid Arthritis to blood cancers such as MDS and AML. With our focus on understanding how genetic variants impact RNA splicing, we can gain insight into human diseases that could lead to new prevention strategies and treatments.

Drugging RNA splicing

Our lab is studying how splice-switching molecules (including small molecules) impact RNA splicing and what potential they have as drugs. Risdiplam’s recent FDA approval is only the beginning – we’re now exploring ways to tune drug specificity to maximize its effect on RNA splicing and gene expression level. We know that risdiplam stabilizes U1 binding to the 5′ splice site of SMN2 exon 7, but we are exploring ways in which to modify specificity and target other disease-relevant genes. Our goal in the next 5-10 years is to design treatments tailored towards modifying expression of many genes through RNA splicing – a game-changing advancement in treatment of diseases.