Mistakes occur during the replication and decoding of the genome. Cells contend with and mitigate the products of such errors through quality control. Quality control can fail in two ways: (1) cells can fail to identify or remove abnormal proteins or (2) cells can inappropriately remove otherwise functional gene products. Both types of failures can cause genetic disease, highlighting the importance of quality control in gene expression. Cells can also exploit quality control for the regulation of ‘normal’ genes. Our research aims to uncover how these surveillance mechanisms work. We hope to pioneer methodologies and models useful for the future study of quality control in gene expression by both scientists and medical researchers. A long-term goal of the lab is to determine how these processes could be enhanced or abrogated to the benefit of human health.
Quality control during gene expression buffers cells from the deleterious products of damage, stress, mutation, and error. Insufficient or overzealous quality control can interfere with normal gene function and yield disease. Alleles that inappropriately bypass or elicit quality control are implicated in, if not causal for, diverse diseases including subsets of Parkinson’s Disease, muscular dystrophies, and hypothyroidism. Basic questions remain unanswered: how do cells discern abnormal from normal gene expression, and by what mechanisms do they remove abnormal gene products? The goal of our work is to understand how cells ensure quality control during gene expression, and how mutations confound quality control and drive genetic disease. Central to this investigation is an understanding of ‘normal’ gene expression, as well as what defines ‘abnormal’ gene expression and its products.
Our research builds on our expertise in RNA and protein metabolism, and uses interdisciplinary approaches to answer focused and genome-wide questions. Our work employs the genetically tractable C. elegans as an opportunity to explore quality control during normal animal physiology, including developmental, behavioral, and cell-specific manifestations. C. elegans work is augmented with studies in human cell lines; our published work illustrates how we leverage experimental fortes of each system. We use whatever techniques are necessary to tackle the question at hand; historically this has included genetic screens, CRISPR/Cas9, biochemistry, molecular biology, with a heavy dose of computational techniques (e.g. sequencing, bioinformatic analyses).