Scientists publish epigenetic research on breast cancer metastasis

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News Article

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School of Medicine & Health Sciences


The research of Assistant Professors Archana Dhasarathy, PhD, and Sergei Y. Nechaev, PhD, in the Department of Basic Sciences at the University of North Dakota School of Medicine and Health Sciences, has been published in Nucleic Acids Research.

Each cell in the body has the same genome or complete set of DNA and all of its genes. And according to its type, each cell follows a distinct regulatory program that involves precisely controlled activation of thousands of genes, and different sets of genes.

For instance, blood cells produce hemoglobin, while pancreatic cells produce insulin; however, both cell types have the same set of genes. The regulation of the specific subset of genes that are expressed from one cell type to the next is known as epigenetics (a combination of the prefixepi, derived from Greek for “above,” and the word genetics). Scientists who study epigenetics look at how genes are expressed (how genes are turned on or off) without affecting the DNA sequence directly.

“How this epigenetic programming works remains one of the most important unsolved questions in biology,” Dhasarathy said. “It holds the key to personalized treatment of diseases such as cancer.”

In their manuscript, Dhasarathy, Nechaev, and their laboratory teams present evidence that the same enzyme that transcribes DNA into specific proteins in cells—RNA polymerase II—may also be involved in epigenetic regulation in cancer metastasis through RNA polymerase II’s additional role in something called transcriptional pausing. RNA polymerase functions by binding to the start site of a gene, called the promoter, and making a single-stranded RNA copy of the DNA, the process called gene transcription. However, this is not a simple process. In many cases, the polymerase pauses a short distance after the start site and waits there until it receives an appropriate signal to move ahead. This is known to be a key step in gene regulation.

In their study, Dhasarathy and Nechaev used a model of breast cancer metastasis, and demonstrated that RNA polymerase can remain paused on genes even during activation to regulate how genes respond to stimuli. In their future research, they plan to use their findings to devise strategies to reprogram cells using epigenetic manipulation for treatment of diseases including metastatic breast cancer.

Epigenetics research generates large amounts of raw data that require analysis by experts in the discipline of bioinformatics—the application of computer, mathematical, and statistical techniques to complex sets of biological data. It was the technology that mapped the human genome. The data generated by the study of the human epigenome dwarf the data produced to map the human genome.

“Our work would not have been possible without a productive and successful collaboration with the Center for Biomedical Research Excellence Bioinformatics Core at the SMHS Department of Basic Sciences and the UND Computer Science Department,” Nechaev said.

Dhasarathy's laboratory team and article coauthors are second-year PhD-student Jessica Warns in the Biochemistry and Molecular Biology Program and Brooke Kubat, a former undergraduate in the laboratory who has been accepted to medical school at UND. Nechaev's laboratory team and article coauthors are PhD-student Ann Samarakkody and postdoctoral-researcher Ata Abbas, PhD. Additional coauthors are Oscar Nnoli, a technician in Nechaev's lab; Bradley Jokinen, an undergraduate student in Computer Science, who worked with Nechaev; Kris Zarns, PhD student in Computer Science; and Adam Scheidegger, UND Epigenetics COBRE Bioinformatics Core.

This research was supported by the National Institutes of Health, the North Dakota Experimental Program to Stimulate Competitive Research, and the University of North Dakota School of Medicine and Health Sciences Faculty Seed Grants.

Nucleic Acids Research publishes the results of leading-edge research into physical, chemical, biochemical, and biological aspects of nucleic acids and proteins involved in nucleic acid metabolism or interactions. Dhasarathy and Nechaev’s research paper, titled “RNA polymerase II pausing can be retained or acquired during activation of genes involved in the epithelial to mesenchymal transition,” is available online at http://nar.oxfordjournals.org/content/early/2015/03/27/nar.gkv263.full.