Profile

The flow of genetic information from DNA to RNA to protein requires the orchestration of specialized proteins that bind to and regulate RNAs. The human genome encodes for over 1,400 RNA-binding proteins, most of whose functions are unknown despite their importance during development and in specific human diseases. The processes by which RNA-binding proteins regulate RNA, collectively known as post-transcriptional gene regulation, permit cells to adapt rapidly to changing environmental cues such that gene expression programs, and thus cellular function, are fine-tuned. For example, post-transcriptional gene regulatory processes serve to mitigate the effects of deleterious stresses that can potentially usurp or disrupt gene expression in cases of bacterial or viral infection, when foreign nucleic acids are introduced into cells. The post-transcriptional mechanisms that prevent aberrant or pathogen gene expression, while still coordinating the expression of host-specific innate immune- and stress-activated genes, remains poorly understood. My laboratory is currently focused on two research areas: 1) To identify and functionally characterize the critical RNA-binding proteins utilized by cells during periods of nucleic acid-induced stress and innate immune gene activation. A key prerequisite for characterizing the function of RNA-binding proteins is to identify its stress-regulated binding targets. My laboratory utilizes RNA biochemistry and molecular biology, in conjunction with modern high-throughput technologies such as PAR-CLIP, to elucidate RNA-protein interactions and gene regulatory function at a transcriptome-wide level. As a complementary approach, we investigate the composition and function of RNA-binding protein complexes (ribonucleoprotein particles) that assemble on specific stress-induced host- or pathogen-encoded transcripts, to understand how such relationships are important for host-cell response and survival. 2) To characterize the components and signaling mechanism of a major cytosolic DNA-sensing pathway. Detection of cytosolic DNA potently activates multiple signaling pathways leading to the transcriptional activation of interferon and stress-activated genes. Thus, the cellular response and gene expression changes associated with DNA-sensing is an ideal model for investigating stress-induced post-transcriptional gene regulatory processes. My laboratory focuses on the innate immune signaling pathway initiated by the DNA sensor and nucleotidyl transferase superfamily member cyclic GMP-AMP synthase, cGAS. Binding of cytosolic DNA to cGAS leads to its production of cyclic GMP-AMP (cGAMP), which I discovered to be the founding member of metazoan cyclical second messenger molecules containing mixed phosphodiester bonds (2’,5’ and 3’,5’). We examine the mechanism of cGAS activation by structure-function and cell biological studies. My laboratory also investigates how natural and synthetic cyclic dinucleotides and related analogs promote innate immune gene activation through the only known cGAMP receptor, Stimulator of interferon genes (STING).

Keywords

cellular DNA-sensing host-pathogen interactions innate immunity PAR-CLIP post-transcriptional gene regulation PTGR RNA RNA-protein crosslinking RNA-protein interactions RNA binding proteins