Overview
The National Cancer Institute (NCI) needed a way to gain greater insight into multiomics data. ESI’s bioinformaticians blended computational and analytical methods to learn more about the link between nitric oxide and methylation, as well as the downstream impact this mechanism has on gene expression and cancer.
Our work shows a new mechanism for nitric oxide in driving cancer, setting the stage for more studies in this area to better understand the molecular changes that promote cancer’s growth and progression.
The Challenge
NCI, the leading federal agency responsible for cancer research at the National Institutes of Health, supports research into the molecular mechanisms underlying cancer. Knowing more about these mechanisms will help NCI find new targets for medications for preventing and treating cancer.
In a recent study, NCI (and NCI-funded) researchers wanted to delve deeper into the mechanisms that drive cancer’s development and progression, but needed specialized data science skills for conducting these analyses. In particular, the researchers knew that nitric oxide impacts a key cellular function (i.e., DNA methylation), which results in aggressive tumors, resistance to treatment, and poor patient prognosis. However, NCI needed additional analyses to further investigate the link between nitric oxide and methylation, as well as the downstream impact this has on gene expression and cancer.
Research into the mechanisms that drive cancer is critical. By targeting these molecular changes, researchers can design more effective cancer therapies.
The Solution
ESI bioinformaticians applied a variety of computational techniques to further uncover the role of nitric oxide in breast cancer:
- DNA methylation. Using Reduced Representation Bisulfite Sequencing (RRBS) data, we identified which sections of DNA were methylated. We mapped those sections to regions that are known to control gene expression (i.e., which promote or enhance expression).
- Gene activity. Using bulk RNA sequencing data, we looked at gene activity. We examined which genes were “turned on,” becoming active (i.e., were upregulated) and which ones were “turned off,” becoming inactive (i.e., were downregulated) when nitric oxide was present.
- Differential analysis. Using DNA regions with fixed methylation states (either methylated or demethylated) as controls, we compared those regions to ones that were either upregulated or downregulated.
Through our analyses, we found that when nitric oxide is present, it results in multiple cancer-driving genes.
The Results
Based on earlier findings, researchers knew that nitric oxide inhibits enzymes (called Ten Eleven Translocation or TET) that are involved in DNA demethylation. We were able to show that inhibiting nitric oxide’s TET effects had a widespread impact on gene expression in breast cancer cells.
This study presents a new role for nitric oxide in cancer. If the study is replicated and extended to tumor samples it will open a new window into how cancer progresses.
To learn more about our approach and the study finding, read the open access journal in Nature Communications.
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