RNA polymerase underlies heritable gene silencing without DNA mutation
By Melissa Lee Phillips | July 21, 2006
Researchers have implicated RNA in epigenetic heredity, according to a report in this week'sNature. RNA polymerase, say the authors, is an essential part of a process in which interactions between two parental alleles influence offspring expression.
Some researchers have suspected that this process, known as paramutation, may involve RNA, said Ting Wu of Harvard Medical School, who was not involved in the study, but "the critical link that [this group has] been able to put through has been lacking."
Led by Mary Alleman of Duquesne University in Pittsburgh, the researchers examined paramutation at the b1 gene in maize, which determines whether a plant's stalk is purple or green. If a plant possesses the dominant allele B-I, its stalk is normally purple. However, if the other chromosome contains the paramutagenic allele B', then B-I's expression is silenced, and the plant appears green. Once B-I expression has been silenced by the B' allele, this state is passed to progeny -- the B-I allele no longer produces purple pigment in future generations, even if the original B' allele is not passed on. "It's as permanent as a mutational change, but there's no change in the DNA," said Viriginia Walbot of Stanford University, who did not participate in the study.
Alleman and her colleagues examined a gene called mop1, which they knew was required for paramutation to occur at the b1 locus. They mapped and cloned this gene and found that it makes an enzyme called RNA-dependent RNA polymerase (RDRP). This RDRP closely resembles a similar enzyme in Arabidopsis that may use short interfering RNAs (siRNAs) to silence chromatin at centromeres.
The maize RDRP may be involved in something similar, senior author Vicki Chandler at the University of Arizona in Tucson told The Scientist. Scientists have shown that a sequence of tandem repeats upstream of the b1 locus is crucial for paramutation to occur: The strength of paramutation correlates with the number of repeats, and alleles that don't participate in paramutation have just one copy of this sequence. It's possible that the RDRP may amplify RNA from this sequence, and that these RNA molecules then alter the chromatin state and silence B-I transcription, Chandler reasoned.
It's not yet clear exactly how the paramutation information is transmitted through meiosis, Chandler said, but two general possibilities exist: Meiosis could transmit the amplified RNA molecules themselves, or it could pass on the RNA-programmed chromatin structure, which would then allow the RNA to be made again.
The researchers could not detect siRNAs from the tandem repeats upstream of the b1 locus, but it's possible that the level was too low, or that larger RNA molecules are involved, Chandler said.
"This paper doesn't really provide the full story," Walbot said, but it connects paramutation to the RNA world. It's "another way that RNA-mediated regulation can occur."
A few cases of paramutation have been reported in species besides maize, including animals, and an RNA mechanism is likely to underlie these cases as well, Chandler said. "It could even underlie other things that aren't recognized as paramutation now, she suggested."
"Paramutation has been one of the most mysterious phenomena involving inheritance," said Harvard's Wu. "The earliest observations were just that something was not being transmitted the way Mendel would have predicted," Wu said. "What that something is has taken a long time to figure out."
Melissa Lee Phillips
Links within this article
M. Alleman et al., "An RNA-dependent RNA polymerase is required for
paramutation in maize," Nature, July 20, 2006.
C.Q. Choi, "RNA can be heredity molecule," The Scientist, May 25, 2006.
L.M. Hrastar, "Is RNA inheritance possible?" The Scientist, March 23, 2005.
S.W. Chan et al., "RNA silencing genes control de novo DNA methylation," Science, February 27, 2004.
L.A. Pray, "Viroids, viruses, and RNA silencing," The Scientist, August 30, 2004.
M. Stam et al., "Differential chromatin structure within a tandem array 100 kb upstream of the maize b1 locus is associated with paramutation," Genes & Development, August 1, 2002.