Genetic Engineering & Biotechnology News

JAN15 2018

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Genetic Engineering & Biotechnology News | GENengnews.com | JANUARY 15, 2018 | 11 tabolomics, or proteomics, to help us understand and inter- pret the differential-expression pattern observed between two conditions," notes Dr. Billaud. The powerful analysis and search tools that are part of the IPA platform can, in the context of biological systems, identify the transcriptional programs that lead to a specific gene-expres- sion pattern and highlight the biological processes involved. IPA relies on the manually curated Qiagen Knowledge Base, which has been in continuous development for more than 15 years and helps place findings into their biological context. In combination with powerful algorithms, IPA provides advanced data analysis and interpretation capabilities and helps generate new hypotheses that can be tested and validated experimentally. At a recent workshop in San Francisco, CA, Qiagen showed how IPA helped identify biological signatures that could distinguish melanoma patients who would respond to immune checkpoint inhibitor therapy from those who would develop resistance (Figure 2). "A key benefit of IPA is the understanding of transcript- level biology as opposed to only the gene-level information," explains Stuart Tugendreich, Ph.D., global product manager of IPA. For years, one of the challenges in data analysis has been the difficulty in analyzing and understanding the bio- logical significance of the hundreds or thousands of different splicing isoforms that are generated by RNA-seq. "IPA functionalities now enable researchers to start look- ing at those splice variants and to begin understanding their biology," adds Dr. Tugendreich. Learning about RNA Decay In the laboratory of Hamed S. Najafabadi, Ph.D., assistant professor in the department of human genetics at McGill Uni- versity, several projects are examining RNA stability and dy- namics in neurodegenerative conditions and cancer. "The main problem that we had during our work was that we could not look at the rate of RNA decay directly," says Dr. Najafabadi. "We had to look at the abundance of RNA instead." "We have been trying to figure out how RNA stability changes across tissues or over time," he continues. "Measur- ing RNA decay rates directly would give us more statistical power and a more direct way to look at the different factors that regulate RNA stability." Historically, looking at the decay of mRNA has been ex- perimentally challenging. In fact, according to Dr. Najafaba- di, anticipating the course of RNA decay can be like guessing the trajectory of a pitched baseball when your only clue is a snapshot of the pitcher. If you look at the ball, and nothing else, you will guess poorly. "But that is what we have done for a long time," insists Dr. Najafabadi. "We have focused only on the abundance of the mature mRNA." Looking at both the hand and the ball, however, can provide insights into the ball's trajectory. "This is what we started to do," maintains Dr. Najafabadi. "By focusing on mature mRNA and pre-mRNA, we found a way to look at the trajectory over time. We can begin to understand how mRNA concentration changes over time and how mRNA degrades." In previous in silico research that separated intronic and exonic RNA-seq reads to dissociate the transcriptional and post-transcriptional contributions to gene expression, it was proposed that exonic reads reflect the steady-state mRNA abundance, whereas intronic changes reflect transcriptional dynamics. "We leveraged this observation and came up with a direct measure of the mRNA decay rate," explains Dr. Na- jafabadi. By decoupling mRNA transcription changes and mRNA decay rates, Dr. Najafabadi and colleagues modeled the kinetics of mRNA metabolism and used a computational approach to estimate the differential mRNA decay rate. LOWEST DEAD VOLUME RESERVOIR ON THE MARKET! SureFlo™ anti-sealing array Save Money On Your Reagents SureFlo TM anti-sealing array ensures the lowest possible dead volume. Eliminate Pipette Head Contamination SureFlo TM array allows pipette tips to sit firmly on the bottom without creating a vacuum. This eliminates the "popping" of fluid into the pipetting head! Visit www.Integra-biosciences.com for your free trial pack! Store it Latching lid prevents spillage and evaporation even when refrigerated! 300 ml 150 ml Visit us at SLAS Booth #1340, February 3-7 San Diego, USA See Taming the Transcriptome on page 12 Drug Discovery Figure 2. This pathway analysis diagram highlights the cytokines and growth factors involved in driving the tumor progression observed in metastatic melanoma patients who exhibit innate resistance to anti-PD1 treatment. Overall, the diagram presents an upstream regulator signature. It was generated by combining technologies from Ingenuity Systems and OmicSoft (both Qiagen companies). For example, Ingenuity Pathway Analysis (IPA), which incorporates a feature called Analysis Match, allowed a search of similar (or dissimilar) activation events across thousands of preanalyzed datasets. This search yielded the upstream regulator signature shown here, a signature that also emerges from other cancer datasets and may serve as a biomarker for predisposition to tumor progression. The underlying dataset is at the Gene Expression Omnibu (GSE78220).

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