We investigate post-transcriptional regulatory mechanisms in bacteria. Our overarching goal is to: (1) develop methods for discovering post-transcriptional regulatory circuitry, (2) examine their biological distribution and molecular evolution, (3) characterize their underlying mechanisms, and (4) assess their potential as drug targets. To date, many different classes of cis- and trans-acting regulatory RNAs have been discovered. In particular, we focus on signal-responsive RNA elements that regulate bacterial gene expression. Many of these genetic elements are used to detect intracellular fluctuations of specific proteins, RNAs, small molecules, or even physical cues, in order to instigate a change in gene expression. Although we are interested in all types of bacterial regulatory RNAs, we focus most on those that function as sensors of intracellular metabolites. These RNA elements, embedded within the 5΄-untranslated region (5΄-UTR) of many mRNAs, adopt three-dimensional shapes that function as high-affinity receptors for specific intracellular metabolite ligands. Binding of the appropriate metabolite elicits a conformational change within the RNA that modifies expression levels of downstream genes. Over 20 separate classes of metabolite-responsive regulatory RNAs have been uncovered and are widely employed for genetic control of fundamental biochemical pathways. Additionally, more than 20 ’orphan’ riboswitch classes have been proposed for regulation of cellular stress responses or coordination of metabolic pathways. Therefore, our analyses of post-transcriptional circuits will continue to yield unique insights into the mechanisms and coordination of microbial stress responses, developmental pathways, and communication networks.
RESEARCH INTERESTS
RNA biology
Biochemistry of gene regulation
RNA structure and function
Posttranscriptional genetic control
Microbial metabolism
RECENT PUBLICATIONS
Wakeman CA, Ramesh A, Winkler WC, "Multiple metal-binding cores are required for metalloregulation by M-box riboswitch RNAs" Journal of Molecular Biology, 392:723-35, 2009
Fox KA, Ramesh A, Stearns JE, Bourgogne A, Reyes-Jara A, Winkler WC, Garsin DA, "Multiple posttranscriptional regulatory mechanisms partner to control ethanolamine utilization in Enterococcus faecalis" Proc Natl Acad Sci USA, 106(11):4435-40, 2009
Collins JA, Irnov I, Baker S, Winkler WC, "Mechanism of mRNA destabilization by the glmS ribozyme" Genes Dev, 21(24):3356-68, 2007
Dann CE, Wakeman CA, Sieling CL, Baker SC, Irnov I, Winkler WC, "Structure and mechanism of a metal-sensing regulatory RNA" Cell, 130(5):878-92, 2007
SIGNIFICANT PUBLICATIONS
Fox KA, Ramesh A, Stearns JE, Bourgogne A, Reyes-Jara A, Winkler WC, Garsin DA, "Multiple posttranscriptional regulatory mechanisms partner to control ethanolamine utilization in Enterococcus faecalis" Proc Natl Acad Sci USA, 106(11):4435-40, 2009
Dann CE, Wakeman CA, Sieling CE, Baker SC, Irnov I, and Winkler WC, "Structure and mechanism of a metal-sensing regulatory RNA" Cell, 130:878-892, 2007
Winkler WC, Nahvi A, Roth A, Collins JA, Breaker RR, "Control of bacterial gene expression by a natural metabolite-responsive ribozyme" Nature, 428:281-286, 2004
Winkler W, Nahvi A, Breaker RR, "Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression" Nature, 419:952-956, 2002
Winkler WC, Cohen-Chalamish S, Breaker RR, "An mRNA structure that controls gene expression by binding FMN" Proc Natl Acad Sci USA, 99(25):15908-13, 2002
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