Making it Rain
UND’s Department of Biomedical Sciences pulls in another $10 million for expanded epigenetics research.
When the human genome was sequenced in 2001, researchers across disciplines had anticipated that determining the function of genes and their components would be a relatively straightforward task.
The instructions for how human beings grow and change turned out to be anything but straightforward, however.
“One of the most exciting things about epigenetics is that the mechanisms are dynamic and reversible, meaning that it is potentially possible to reprogram a faulty epigenome back to a normal or healthy state,” explained Roxanne Vaughan from her office at the UND School of Medicine & Health Sciences (SMHS), describing how the research that followed this sequencing breakthrough showed that the expression of genes is extremely complex, differing across cell and tissue types, throughout embryonic development and maturation, and in disease conditions.
“This fuller understanding of gene function requires knowledge of not only what products are encoded by genes, but how expression of the gene is regulated in specific conditions,” she said.
Thus was the field of epigenetics born.
Researchers studying epigenetics explore the mechanisms that regulate gene expression and the activation and deactivation of specific genes. Understanding better how the human body can turn genes on and off during growth and aging and in response to its environment has important implications for the diagnosis and treatment of many disorders including cancer, diabetes, major depression, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
The Human Genome Project notwithstanding, then, the apparatuses underlying these pathologies remain poorly understood and represent a continuing gap in scientific knowledge. To that end, the Epigenetics Working Group (EWG) at the University of North Dakota was formed in 2013 through the support of a $10 million Center of Biomedical Research Excellence (CoBRE) grant from the National Institutes of Health (NIH) to investigate such questions.
This initial award helped five junior investigators at UND establish research projects that allowed them to compete successfully for larger grants. These researchers have already published 61 papers and received approximately $5.5 million in additional funding from the NIH, the National Science Foundation, and private foundations. Furthermore, the grant helped establish a Genomics Core at UND, which has been used by researchers from 32 individual labs, with over 5,000 genetic samples processed for genome-wide analyses.
So successful have Dr. Vaughan and her colleagues been at exploring the epigenetics of disease at UND that the NIH recently awarded the SMHS a second $10 million, five-year grant to bolster and expand the School’s epigenetics research program.
“This new ‘CoBRE-II’ will help another set of investigators establish research in their field,” continued Vaughan, principal investigator of the CoBRE grant and Chester Fritz Distinguished Professor at the SMHS. “The new group of investigators funded include Drs. Keith Henry, John Watt, and Motoki Takaku from the SMHS, and Drs. Diane Darland and Manu from the UND Department of Biology. Because epigenetic changes are potentially reversible, this group’s research could lead to new therapeutic paradigms for pathologies that have thus far resisted treatment or cure.”
Takaku, a newer faculty member at UND who has built a career working on chromatin enzymes, stresses the significance of this grant for his work on breast cancer.
“Many chromatin associating proteins are frequently mutated in cancer,” he explained. “This is a very new area in cancer therapy, and at least one company sees a $40 billion market value in this area. We are trying to understand the fundamental mechanisms of chromatin organization as well as disorganization in cancer. This grant helps our progress on this study.”
Darland agreed, arguing that the grant renewal is a watershed, without which she would not be able to complete her research that takes a genome-wide approach to investigating critical questions concerning neural-vascular interactions in development and disease.
Drs. Takaku, Manu, and Darland
“My primary interest is in stem cell and blood vessel interactions during development and in glioma tumor progression,” she noted, describing the type of tumor that starts in the glial cells of the brain or the spine. “Glioma is among the most common and lethal malignant brain tumor type in the United States, and glioma cell interactions with the surrounding vasculature are thought to be critical for both diseased cell dispersal within the brain as well as the potential conduit for therapeutic intervention.”
“This grant will allow our lab to establish a new line of investigation tackling an important unsolved problem: how do genes integrate signals from multiple sources,” added Department of Biology Professor Manu. “Lying near most genes in our genome are DNA sequences called enhancers. Although we know how individual enhancers control genes, we don’t understand how genes integrate signals from multiple enhancers. This problem is important for understanding leukemogenesis, since genome rearrangements in cancer cells align genes with enhancers, causing the genes to be expressed [problematically].”
Takaku, Manu, and Darland are but three faculty among more than a dozen whose work has benefitted directly from the university’s decision to focus on epigenetics and epigenomics over the past decade.
“Epigenetics and Epigenomics research at UND has simply exploded since the first CoBRE Phase I grant was awarded, and I anticipate an even greater expansion now that the Phase II has been funded,” Darland added. “We have brought on so many new investigators into the group from new hires, to internal collaborations, to building professional networks across the region. These types of expanding research conversations will not only bring recognition to the high quality of research being conducted at UND, but also will allow us to conduct timely and important research regarding the epigenetics of development and disease. It’s an exciting time to be part of the research team!”
It is an exciting time in biomedical sciences, admitted Vaughan, in so far as epigenetics seems to be the hub around which many—if not most—of the biomedical research projects at universities and research facilities around the world rotate these days.
“[Epigenetics] isn’t ‘everything,’ but these mechanisms are fundamental to multiple types of tissues and most cell types,” she said. “Epigenetics scientists utilize approaches from many disciplines including biochemistry, molecular biology, and cell biology to address questions about how genes work in normal and disease pathology. And that cross-disciplinary character in science is the future.”