At a Feb. 5 Duke University seminar, NIEHS biochemist Trevor Archer, Ph.D., discussed “Using Epigenetic Enzymes to Regulate Transcription.” Archer, head of the NIEHS Chromatin and Gene Expression Group, was introduced by Duke associate professor Joel Meyer, Ph.D., who is a former postdoctoral researcher at NIEHS.
Archer said that present-day studies of epigenetics focus on heritable changes in gene function that occur with no change in the sequence of DNA. These changes determine whether the proteins that specific genes code for are actually produced in the cell.
Chromatin and accessibility to transcription
Epigenetics helps explain why cells with the same DNA develop different functions in the body. “And that process may arise from different chromatin states,” Archer suggested. Chromatin, which refers to the packaging of DNA and histone proteins, allows DNA to be compacted into a very small space and form chromosomes.
“While it [DNA] is compacted, it has to remain or become accessible to various actors, including transcription factors, which can then stimulate the production of RNA,” he explained, adding that many epigenetic enzymes play important roles.
Archer’s group is interested in nuclear receptors, a family of transcription factors that are particular targets for endocrine disruptors. “Many of the [environmental] compounds we’re interested in interact with members of this family of transcription factors,” he said, listing health consequences that range from arthritis and immune system defects to breast cancer and other hormone-dependent cancers.
Wine, terroir, and epigenetics
To figure out how enzymes regulate transcription, Archer’s team first needed to determine how a receptor interacts with the genetic, or chromatin, landscape. Once they understood that, they could then discover how the chromatin remodelers regulate transcription.
Introducing a slide showing the lush landscape of the Willamette Valley wine region in Oregon, Archer discussed the notion of terroir, which refers to the influence of a particular region on the wines made from the grapes that grow there. Terroir is analogous to epigenetics, he told the audience of students and faculty. “Epigenetics is going to regulate everything you are interested in.”
The scientific process at work
Archer’s talk skillfully portrayed the scientific process his lab followed, with researchers asking, and finding answers to, a series of progressively more precise questions. While discussing how a protein known as the BRG1 complex interacts with the glucocorticoid receptor, he described a sequence of discoveries about why receptors bind at certain sites, how that binding results in changes to chromatin architecture, and how those changes affect transcription, or gene expression.
This process has led to greater understanding of the roles of certain proteins. For example, he described how KU70, a protein that has been studied with connections to certain autoimmune diseases, was found to be involved in repairing DNA breaks.
Archer highlighted the importance of quick repair of DNA breaks, by pointing out that in the time he had been talking, listeners had probably experienced hundreds of thousands of DNA breaks. “But we’re all still here so they have been repaired,” he said.