Harvard Stem Cell Institute (HSCI) researchers have settled a century-old debate over whether occurrence of DNA methylation acts to silence gene expression, or if genes are turned off by other means before they are methylated.
As explicated today in the journal Nature, methylation in fact enforces gene silencing, and it is levels of a newly identified form of RNA produced by individual genes that determines whether they are turned off by the addition of a methyl (CH3) group by the enzyme DNA methylase 1 (DNMT1).
The study, led by HSCI Principal Faculty member Daniel Tenen, MD, found that during transcription of DNA to RNA, a gene produces a small amount of what the investigators named "extracoding RNA," which stays in the nucleus and binds to DNMT1, blocking its ability to methylate, or silence the gene. The discovery of RNA's new function has therapeutic potential as an on-off switch for gene expression.
"We have demonstrated, at least for one gene in detail, and probably thousands more, that extracoding RNA serves to protect the gene from methylation," said Tenen, who heads laboratories at Beth Israel Deaconess Medical Center and the Cancer Science Institute of Singapore, where he is director, at the National University of Singapore. "When the RNA is shut off, which we did by various means, the gene becomes methylated."
Postdoctoral fellow Annalisa Di Ruscio, MD, PhD, and laboratory staff member Alexander Ebralidze, PhD, were major contributors to the work.
The biological irony is that DNMT1 has long been considered a DNA-binding enzyme, so it is surprising that it is able to bind so well to extracoding RNA, Tenen explained.
"If you put extracoding RNA into a cell, you can actually inhibit the ability of DNMT1 to maintain methylation patterns of that gene and induce demethylation in a gene-selective manner," Tenen said. "The reason this is interesting is the cancers and other disease are treated using demethylation agents, so this gives us the opportunity to try to direct gene-specific demethylation."
This work was supported by the National Institutes of Health, the Italian Foundation for Cancer Research, Fondazione Roma, an American Italian Cancer Foundation Fellowship, the Singapore National Research Foundation, the Singapore Ministry of Education, and the Singapore Ministry of Health.
- Annalisa Di Ruscio, Alexander K. Ebralidze, Touati Benoukraf, Giovanni Amabile, Loyal A. Goff, Jolyon Terragni, Maria Eugenia Figueroa, Lorena Lobo De Figueiredo Pontes, Meritxell Alberich-Jorda, Pu Zhang, Mengchu Wu, Francesco D’Alς, Ari Melnick, Giuseppe Leone, Konstantin K. Ebralidze, Sriharsa Pradhan, John L. Rinn, Daniel G. Tenen. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature, 2013; DOI: 10.1038/nature12598
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