SCIENCE & TECHNOLOGY
GENE CONTROLLERS
happen in genes that can be easily turned on and off,” he says. However, Corey expects this mechanism will not be limited to one type of gene. “We’ve done computational searches of promoter sequences against known microRNAs” to try to identify potential ones that actually behave as agRNAs, he says. MicroRNAs are endogenous RNAs that are similar in length to agRNAs and are found throughout the genome. “The number of excellent matches that we’re getting computationally with gene promoters and microRNAs is going
RNA-CONTROLLED GENE EXPRESSION
Activation Noncoding RNA transcript
Target of transcription-altering synthetic RNA is ANOTHER KIND OF RNA
hnRNPk
AGO agRNA
hnRNPk
Pol II HP1
Silencing
RESEARCHERS HAVE identified the tar-
get of synthetic RNAs that can turn gene transcription on and off, a finding that could lead to new ways of controlling gene expression in cells. The lab-made RNAs with transcriptionaltering ability, known as antigene RNAs (agRNAs), are short pieces of doublestranded RNA that are complementary to regions of genomic DNA that promote gene transcription. They can inhibit or activate gene expression, depending on the circumstances (C&EN, Feb. 5, 2007, page 8, and Aug. 8, 2005, page 10), but their molecular targets have remained unknown. Now, the same team that first synthesized agRNAs, led by David R. Corey and Bethany A. Janowski of the departments of pharmacology and biochemistry at the University of Texas Southwestern Medical Center, Dallas, shows that agRNAs bind to so-called noncoding RNA transcripts, which are non-protein-coding single-stranded RNAs with sequences partially complementary to those of gene promoters (Nat. Struct. Mol. Biol., DOI: 10.1038/nsmb.1444). In subsequent steps of gene activation or inhibition, the agRNA recruits Argonaute proteins (catalytic RNA-binding proteins) to the noncoding RNA transcript, and the resulting complex acts as a scaffold for other transcription factors.
“This paper represents another big step forward in the exciting, rapidly evolving field of RNA-controlled gene expression,” says Anna K. Mapp, an associate professor of chemistry and medicinal chemistry at the University of Michigan, Ann Arbor, who studies the regulation of gene transcription. “Janowski and Corey have addressed a key question regarding the function of antigene RNAs as upregulators and downregulators of transcription by identifying a molecular target.” Using the progesterone receptor as a model system, Corey and Janowski’s team confirms that agRNAs activate or inhibit gene expression in different circumstances. In a breast cancer cell line that expresses high levels of the receptor, agRNAs inhibit gene expression. In another breast cancer cell line that expresses low levels of the progesterone receptor, the agRNAs activate gene expression. In both cases, noncoding RNA transcripts must be present for agRNA to work. COREY POINTS OUT that such activity is
reminiscent of hormone-mediated gene regulation, in which small-molecule ligands can increase or decrease expression levels. “The fact that you can get activation and repression in different circumstances may be something that is more likely to WWW.C E N- ONLI NE .ORG
J ULY 2 1 , 20 0 8
Noncoding RNA transcript
hnRNPk
AGO agRNA Pol II
hnRNPk
HP1
ON/OFF SWITCH agRNAs control gene expression by binding to noncoding RNA transcripts and recruiting Argonaute (AGO) proteins to the promoter region of DNA. The complex serves as a scaffold for recruiting or redirecting other proteins, such as hnRNPk and HP1G, or the transcription enzyme RNA polymerase II (Pol II). Solid lines denote factors that associate and dashed lines factors that dissociate with promoter DNA. up very quickly. There are a lot of candidate genes out there” that may be controlled by agRNAs, he adds. The next step is to find those endogenous agRNAs, Corey says. “The most important thing is to establish with a high degree of evidence that there are natural antigene RNAs” that actually exist in living cells, he says. “There’s a fair amount of skepticism about it. We accept that, and we’re going to set a high bar for this work.”—CELIA ARNAUD
NAT. ST RUCT. MOL. BIOL.
DAVID G R ES HA M /U T SOU THW ESTER N
Corey (left) and Janowski discuss their agRNA research.
