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).