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TECH TIPS OMICS cancer survival. The investigators hypothesized that the few key chromosomal regions whose methyla- tion is required for cancer cell survival would preferentially remain methylated when global methylation levels are reduced. After surveying residual DNA methylation levels in cancer cells with genetically disrupted DNA methyltrans- ferases and clustering profiles from normal cells and primary cancer tissues, Dr. Jones and colleagues used gene expression meta-analysis to define the regions that are dependent on DNA methylation-dependent gene silencing. Their strategy helped identify a set of promoters whose methylation is required for somatic cancer cell survival. Some of the respective genes are shared among several tumor types, while others are cancer- or tis- sue- specific. "The genes identified by this ap- proach have not been previously known as tumor suppressor genes," notes Dr. Jones. In addition to helping define and validate the minimal DNA methylation profile that is necessary and functionally relevant for cancer cell survival, this approach advances our knowledge on the molecular events that drive cancer development, and promises to define a new generation of epigenetic thera- pies, in which the alterations that are being targeted are exactly the ones that the cancer cells rely on for survival. While over the past 15 years the field of DNA methylation has focused on pro- moters, there are additional regions where methylation, even though not well under- stood functionally, could play important biological roles. "We are looking more globally to see whether the bodies of the genes and the en- hancers, which also undergo methylation, but we do not know yet it role at these loca- tions, is important. It is important to look beyond promoters," says Dr. Jones. A significant challenge in biomedical sci- ences emerged when functional genomics de- velopments, which uncovered novel aspects about biological systems, have not been par- alleled in pace by drug discovery advances. "Another problem is that the current strategy of optimizing candidate therapeutic compounds, which relies on a single target, is somewhat dangerous, and measuring the collective response of all relevant genes relat- ed to a specific phenotype, which is a much better option, has been technologically chal- lenging," says Xiang-Dong Fu, Ph.D., pro- fessor of cellular and molecular medicine at the University of California, San Diego. RASL-Seq To address this challenge, Dr. Fu and col- leagues recently developed and described RASL-Seq, a new massively parallel quantita- tive gene analysis strategy in which RNA-me- diated oligonucleotide annealing, selection, and ligation are coupled with next-generation sequencing, allowing hundreds of genes to be followed concomitantly under thousands or tens of thousands of distinct conditions. RASL-Seq helped investigators in Dr. Fu's lab develop a high-throughput sequencing method, which allows multi-target drug de- Genetic Engineering & Biotechnology News sign to be performed in a pathway-centric, high-throughput fashion, a strategy neatly designed for the study of small molecules that affect disease-specific gene expression pathways. The fact that specific drug targets do not need to be identified in advance repre- sents one of its advantages over conventional chemical screening. Dr. Fu and colleagues illustrated the pow- er of this technique in a study that sought to identify small inhibitors of androgen receptor-mediated gene expression for treat- ing hormone-refractory prostate cancer and identified several classes of compounds. One of them, a cardiac glycoside, inhibited both androgen-sensitive and androgen-resistant prostate cancers without exhibiting severe cytotoxicity, and this effect most likely oc- curred through the proteasome-dependent degradation and destabilization of the an- drogen receptor. "This approach brings a unique advan- tage when studying complex diseases be- cause of the multitude of pathways that are involved. It may contribute to an integrated pattern of gene expression," explains Dr. Fu. In another study using RASL-Seq, in- vestigators in Dr. Fu's lab blocked different branches of EGF-induced signaling and un- See Gene Expression on page 38 Quantify, verify, In science there are always essential steps in any workflow. 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