RNA Structure and Viruses
RNA viruses have small genomes and encode relatively few genes, yet are capable of extensively highjacking the cellular host machinery. In addition to storing genetic information, RNA genomes are known to fold into 2 and 3-dimensional structures critical for the viruses. Our lab’s focus is on how different structural elements in the viral genome impact its life cycle and ability to survive in hosts.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2)
Amidst the COVID19 outbreak, our lab is currently prioritizing probing the structure of the entire SARS-CoV2 30kb genome in vivo, including structures in the 5’UTR and frameshift element which are important for virus replication and survival. Like many others, we hope to contribute towards scientific understanding of this virus and share what we learn as quickly as possible.
Human Immunodeficiency Virus-1 (HIV-1)
HIV-1 must express all of its gene products from the same 10-kb single-stranded RNA primary transcript, which undergoes alternative splicing to produce diverse protein products. Despite the critical role of alternative splicing, the mechanisms driving splice-site choice are poorly understood. Previous work on the genome-wide HIV-1 RNA structure in vitro and in virion provided a population average model. Our lab, however, probed the structure of HIV-1 RNA in cells and revealed the importance of alternative conformations assumed by the same RNA sequence in the virus.
Alternative Splicing and RNA Structure in Humans
Gene expression and its regulation are at the heart of biology and disease. For humans, alternative splicing expands proteomic diversity by an order of magnitude. It is central to establishing the identity of the many types of cells in the human body. In addition to normal development, it is estimated that 20-50% of all human genetic diseases result from mutations that cause errors in alternative splicing, including many cancers and neurodegenerative diseases. Despite the importance of alternative splicing in physiology and disease, we lack a mechanistic and predictive understanding of how cells make alternative splicing decisions.
Our lab investigates co-transcriptional RNA folding at splice sites in vivo. A simple model of alternative splicing regulation is that RNA folding can occlude or expose these sequence features thereby promoting or inhibiting splicing. Regulation of human splicing by RNA structure is a long-standing hypothesis, with indirect evidence, and has remained unexplored due to technical limitations. Our goal is to provide quantitative models for RNA folding and RNA-protein interactions that predict cell-type specific and disease-specific alternative splicing on a genome-wide level.
