Public release date: 26-Jun-2012 [ | E-mail | Share ]

Contact: Jim Fessenden james.fessenden@umassmed.edu 508-856-2000 University of Massachusetts Medical School

WORCESTER, MA Organisms employ a fascinating array of strategies to identify and restrain invasive pieces of foreign DNA, such as those introduced by viruses. For example, many viruses produce double-stranded (ds)RNA during their life cycle and the RNA interference (RNAi) mechanism is thought to recognize this structural feature to initiate a silencing response.

Now, UMass Medical School researchers have identified a mechanism related to RNAi that scans for intruders not by recognizing dsRNA or some other aberrant feature of the foreign sequence, but rather by comparing the foreign sequences to a memory of previously expressed native RNA. Once identified, an “epigenetic memory” of the foreign DNA fragments is created and can be passed on from one generation to the next, permanently silencing the gene.

A remarkable feature of this RNAi-related phenomenon (referred to as RNA-induced epigenetic silencing, or RNAe), is that the animal carries a memory of previous gene expression. This memory of active genes serves as an “anti-silencing” signal, which protects native genes from RNAe and under some circumstances appears to adopt foreign genes as self. These findings, described in three studies (including a study by Eric Miska and colleagues of the Gurdon Institute, University of Cambridge and Wellcome Trust, UK) published online yesterday and to appear in the July 6 issue of Cell, provide new insights into how identical organisms can have the same DNA sequence but opposite patterns of gene expression and thus dramatically different phenotypes.

“If a worm modulates gene expression by carrying a memory of the genes it expressed in previous generations, perhaps other organisms (including humans) can as well. If so, mechanisms of this type could have an important impact on evolution,” said Craig C. Mello, PhD, Howard Hughes Medical Institute Investigator, Blais University Chair in Molecular Medicine and distinguished professor of molecular medicine and cell biology. “The RNAe mechanism could accelerate evolutionary change by increasing heritable phenotypic variation (without the need for DNA mutations). There is growing evidence that many organisms can track and respond epigenetically to gene expression patterns. Our findings provide insight into a whole new level of sophistication in the recognition and memory of gene expression programs.”

Dr. Mello and colleagues knew that when a foreign piece of DNA encoding the green fluorescent protein, or GFP, was inserted into the small roundworm C. elegans, some of the worms would silence the newly introduced DNA while others would express the GFP gene. They then explored a role for RNAi in the decision to silence or express GFP. RNAi is a process whereby cells modulate the activity of their genes. In RNAi-related phenomena, Argonaute proteins interact with and use small RNAs as little genetic guides to recognize target nucleic acids through base-pairing interactions.

Based on their findings, Mello and colleagues posit a model comprised of three separate Argonaute systems that work together to scan, identify and silence foreign DNA, while protecting the expression of normal genes. In this system, an Argonaute called PRG-1 (Piwi) bound to piwi-interacting RNA (piRNA) is responsible for scanning molecules of RNA as they leave the nucleus of the cell and determining if they are indigenous to the organism or foreign. If PRG-1 and its piRNA cofactors identify a foreign sequence, it initiates (or activates) the second Argonaute system, known as WAGO, which turns the genetic material off so it can’t be expressed.

Once the DNA is identified as foreign and silenced, an epigenetic memory is created that silences the foreign gene from one generation to the next. While the inheritance of this memory requires further exploration, the authors showed that successive generations of C. elegans are unable to express the foreign DNA even if the corresponding piRNA is absent.

“It appears that piRNAs are responsible for the initial scanning and identification of foreign nucleic acids,” said Darryl Conte Jr., PhD, research assistant professor of molecular medicine and one of the co-authors on the Cell papers. “Because the foreign DNA in successive generations is being silenced, even in worms that don’t have the piRNA, the information necessary for silencing is being passed on epigenetically and independently of the initial scanning done by the piRNA complex in the previous generations.”

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