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Unlocking the Methylation Mystery

  • Title: Assistant Investigator, The Institute for Genomic Research
  • Education: PhD, University of Buenos Aires, 1996; Fellow, Cold Spring Harbor Laboratory
  • Recommended by: Claire Fraser-Liggett, Robert Martienssen

Kicking off his career with a project that may have been enough to drive other people away didn't faze Pablo Rabinowicz. He started working on the maize genome during his postdoc with Robert Martienssen at Cold Spring Harbor Laboratory and acknowledges that the bench work might have turned most people off. “In the beginning, for somebody with not much experience in genomics, it might seem boring to work on [such a] large-scale, simple problem,” he says. “But I found it interesting to look at genomes from a big perspective, rather than a single gene.”

So began his interest in elucidating the large genomes of two potential biofuel sources: maize and the castor bean — with an eye toward how these plants tolerate such large genomes. Like many plants, the maize genome is predominately composed of retro-transposable elements that are most likely silenced epigenetically in order to avoid significant genomic damage. That makes targeting gene-rich regions much more practical than whole genome sequencing. To this end, Rabinowicz employs methylation filtration, a targeting method he helped develop while still at Cold Spring Harbor. “It's basically a means for selecting genes out of large genomes in an efficient way,” he says. “Therefore, you can clone and sequence genes more efficiently than in a whole genome shotgun approach.”

Methylation filtration is based on a protein system in E. coli that recognizes and destroys incoming foreign DNA only if it is methylated. As most plant genes are unmethylated, a clone of plant DNA can be made in E. coli, recovered, and then sequenced. Methylation filtration also screens out repetitive DNA, which is often methylated, thereby lowering the proportion of repetitive DNA in a methylation filtration library.

Rabinowicz's other focus, the castor bean, is perhaps best known as a ricin toxin-producing plant, despite its potential as a biofuel. “The goal of castor bean as a crop is to produce high-quality oil,” he says. “But because of this toxicity, the production of the crop is minimized and the oil is imported.” Due in part to these biosecurity interests, the National Institute of Allergy and Infectious Diseases recently funded Rabinowicz to sequence the castor bean genome at a low-pass coverage. But when the time comes that there really is a need to tap biofuel sources like the castor bean, plant genomics will be there to help, says Rabinowicz. “When that happens, knowing the genetics and genomics of the plant will allow you to improve whatever problem you have at that time,” he says. 

Looking ahead

With large genomes comes a need for substantial funding. Rabinowicz says there is funding for crops native to the US, like maize, but money for researching a tropical plant like castor bean is hard to come by. He hopes that if, at some point, the necessity for biofuel ends up requiring tropical crops, research will have already been funded before it's too late. “You should start earlier … to cover the knowledge so when the moment comes to use those crops, you already know how to modify them,” he says.

Publications of note

Rabinowicz and Martienssen published a Nature Genetics paper in 1999 entitled “Differential methylation of genes and retrotransposons allows shotgun sequencing of the maize genome,” describing methylation filtration as an efficient method to clone and sequence genes while avoiding unwanted repetitive DNA. In 2003, they published “Maize genome sequencing by methylation filtration” in Science, a follow-up study showing that methylation filtration is still effective when conducted at a large scale, on the order of 100,000 sequences.

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