P&S Journal: Fall 1996, Vol.16, No.3
Genomic Methylation for AIDS and Cancer Therapies
Researchers have taken the first steps in developing therapies for AIDS and cancer that rely on a naturally occurring defense system within cells. This defense system, which is based on methylation of cytosines in DNA, is being used to inactivate deleterious genes. In an April issue of Nature Genetics, Dr. Timothy Bestor, associate professor of genetics and development, discussed the possible biological roles of genomic methylation patterns.
Methylation is a process in which methyl groups are attached to cytosine residues in DNA, shutting off the expression of a gene. The exact function of this process is not entirely clear. One possibility is that methylation turns genes on and off during an organism's development. Methylation may also act as a genomic defense system by restricting the transcription of parasitic sequence elements-stretches of DNA that have been incorporated into the genome from either outside sources or transcription errors and that are potentially harmful if activated.
Without the methylation defense system, the sequence elements would proliferate unchecked and might impose a lethal mutagenic or cytotoxic burden, says Dr. Bestor. For instance, Drosophila (common fruit flies) lack methylated bases in their DNA and also suffer from more mutations due to the insertion of parasitic genes than animals with methylated genomes. In addition, when researchers treat cells or mice with drugs that demethylate the genome, the result is activation of previously silent retroviruses and endogenous genes. Because a large part of the genome represents parasitic sequences that, if activated, would not be recognized by the immune system, a genome host defense system based on methylation makes sense in evolutionary terms, says Dr. Bestor.
Dr. Bestor has cloned and sequenced mammalian DNA methyltransferase and used gene disruption techniques to show that DNA methyltransferase protein is required for mammalian development. Furthermore, in preliminary work with targeted methylation, Dr. Bestor, Dr. Guo-Liang Xu, a postdoctoral fellow, and Michael Livstone, a graduate student, are developing CpG-specific DNA methyltransferase of novel sequence specificity that can be directed to a single promoter that controls the expression of viral DNA or other deleterious genes.
If this technology can be further developed and harnessed, it holds great promise for reducing the severity and incidence of a number of diseases by shutting off the genes that are involved in specific diseases, says Dr. Bestor. For instance, only a single promoter is required for the replication of HIV; methylation of this DNA could effectively shut down the virus. Potentially, methylation could be used as a treatment for AIDS, hepatitis B, and human papilloma virus infection.
Dr. Bestor is optimistic about the development of this technology. Methylation stimulates an existing host defense system and does not depend on a highly artificial system in order to work. Also, once a new methylation pattern is imposed on a promoter, the cellular mechanism keeps it intact. Therefore, any therapeutic agent used to methylate a target sequence would only have to be present for a brief period. Finally, Dr. Bestor notes that a genomic host defense system based on methylation will also have consequences for gene
therapy, since the mechanism could conceivably inactivate replacement genes. "Successful gene transfer may require the development of delivery vectors that evade the silencing response that is based on DNA methylation," he says.