We launched the Regulator Effects in Ingenuity Pathway Analysis (IPA) last year, and it’s been so gratifying to see how helpful this new feature has been for users of the application. It integrates results from our Upstream Regulator and Downstream Effects tools, creating hypotheses to explain what’s going on upstream that may be causing a phenotype or other functional outcome. With Regulator Effects, IPA users can identify potential mechanisms behind a phenotype, identify drug targets, and determine the biological impact of upstream molecules according to the genes they regulate.
Already, a number of publications have described interpretation advances based on Regulator Effects. Below you can find a short description of two of these articles. If you’d like to learn more about IPA, you can sign up for our webinars here.
CEMP1 Induces Transformation in Human Gingival Fibroblasts
First author: Mercedes Bermúdez
In this PLoS One paper, scientists from Mexico and the U.S. investigated the potential of CEMP1, an important regulator in tooth formation, for bone regeneration and other treatments. Starting with gene expression profiles, they found that CEMP1 modifies several genes, many of them linked to oncogenesis. “We also determined that the region spanning the CEMP1 locus is commonly amplified in a variety of cancers, and finally we found significant overexpression of CEMP1 in leukemia, cervix, breast, prostate and lung cancer,” the authors report. “Our findings suggest that CEMP1 exerts modulation of a number of cellular genes, cellular development, cellular growth, cell death, and cell cycle, and molecules associated with cancer.” The scientists note that further study is needed to determine whether CEMP1 is a novel oncogene or simply a passenger linked to another driver gene.
The team used IPA to analyze the genes identified by gene expression analysis. With Upstream Regulator Analysis, they were able to identify two potential upstream regulators: a beta-catenin protein involved in the Wnt signaling pathway, and a transcription factor known to mediate apoptosis and cell proliferation.
Inhibiting the Mammalian Target of Rapamycin Blocks the Development of Experimental Cerebral Malaria
First author: Emile Gordon
Scientists from the National Institute of Allergy and Infectious Diseases published in mBio their findings from studying a mouse model of cerebral malaria. They tested rapamycin, an mTOR inhibitor, and determined that outcomes improved significantly when treated with the medication within four days of infection. “Treatment with rapamycin increased survival, blocked breakdown of the blood-brain barrier and brain hemorrhaging, decreased the influx of both CD4+ and CD8+ T cells into the brain and the accumulation of parasitized red blood cells in the brain,” the team reports.
They analyzed transcriptional patterns caused by rapamycin to understand its effect, which suggested that leukocyte activity in the brain was blocked by the medication. “Remarkably, animals were protected against cerebral malaria even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen,” the scientists note.
The team used IPA to identify enriched pathways, characterize networks, and predict upstream regulator effects for the differentially expressed genes they found in a comparison of untreated to treated mice. Regulator Effects features allowed the scientists to predict networks interrupted by rapamycin, identifying cellular invasion and lymphocyte proliferation, among others, as key functions inhibited by the treatment.