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RNAi Helps Restore Some Lost Epigenetic Marks, Study Finds

NEW YORK (GenomeWeb News) – A cell's RNA interference machinery can help restore lost epigenetic marks across generations in Arabidopsis, according to a new study appearing online today in Science Express.

A team of researchers from several European institutions compared the cytosine methylation patterns at transposable elements and other repeat regions in wild type Arabidopsis thaliana, mutants with methylation defects, and progeny from crosses between the two. They found that methylation could actually be restored in certain, heavily methylated, sites in the genome across the generations — but this process depended on RNAi pathways.

"[W]e demonstrate the existence of an efficient mechanism that protects against trans-generational loss of DNA methylation in Arabidopsis," senior author Vincent Colot, a genomics researcher at France's National Center for Scientific Research, and colleagues wrote. "Remethylation is specific to heavily methylated repeats that are targeted by the RNAi machinery."

Even though epigenetic processes are highly regulated, cells can lose methylation and other signals during mitosis or meiosis. And certain mutations contribute to this loss. For instance, previous research suggests Arabidopsis plants with mutations in the methyltransferase gene MET1 or the ATPase chromatin-remodeling gene DDM1 are prone to DNA methylation losses of more than 70 percent.

And at least some of these losses are carried over to progeny resulting from crosses between mutants with methylation defects and wild type cells. That led to the theory that, once lost, DNA methylation could not be restored. But the researchers reasoned that since the methylation of repeat elements is usually pretty stable from one generation to the next, there must be a way to maintain and re-establish this methylation.

Indeed, when they used quantitative PCR to examine transposable and other repeat elements of wild type Arabidopsis and ddm1 mutant progeny, the researchers found that methylation could be restored across generations. For the repeats tested, nearly half of those that had been hypomethylated in the ddm1 mutant were remethylated to wild type patterns after five generations.

Similarly, subsequent experiments suggested that F1 plants generally had methylation levels somewhere between that of their wild type and ddm1 mutant parents.

And when the team compared the small RNA repertoires of wild type and ddm1 mutants, based on published deep-sequencing studies, they found that remethylatable sequences tended to correspond to 24-nucleotide small RNAs in wild type cells.

On the other hand, ddm1 mutants had a different distribution of some small RNAs — in particular, they tended to have a preponderance of 21-nucleotide small interfering RNAs associated with specific sequences. Those and other experiments led the researchers to the conclusion that RNA interference is critical in the remethylation process.

"Although the frequency with which DNA methylation can be lost in natural settings is unknown, our discovery of a corrective mechanism reveals an important role for RNAi in protecting the genome against trans-generational epigenetic defects," they concluded. "This mechanism also has potential adaptive and evolutionary implications, by allowing the generation of epialleles with differences in trans-generational stability."

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