Peter Dempsey, PhD, professor of pediatrics-developmental biology in the CU School of Medicine, and Justin Brumbaugh, PhD, assistant professor of molecular, cellular, and developmental biology at CU Boulder, recently published a paper in the journal Nature Cell Biology showing the importance of the H3K36 methylation process in regulating plasticity and regeneration in intestinal cells.

“The intestine has an enormous ability to regenerate itself after injury, and it does this through a model of dedifferentiation,” Dempsey explains. “The cells dedifferentiate back into a type of regenerative stem cell after injury, and those stem cells eventually recover the intestine and turn back to normal cells.”

Finding the switch

Scientists have been looking for a long time for the “switch” that turns regular intestinal cells back into regenerative stem cells, Brumbaugh says. Using animal models, he, Dempsey, and the rest of their research team found that H3K36 methylation — a biochemical process that occurs within the H3 histone protein — is responsible for turning that plastic state on and off. Their research was funded by a grant from the CU Cancer Center.

“If you think about it, those cells that are normally in the intestine have to maintain their identity so they’re functional,” Brumbaugh says. “You have to be sure that they don’t flip when they’re not supposed to, because you lose their specialized function — which is also a hallmark of cancer. There has been other research on histone modifications, because epigenetics makes sense to study in this context. It makes sense that you have this form of regulation that will prevent reversion and lock in cell fate.”

Next steps

With H3K36 methylation identified as the process responsible for the switch between normal cells and regenerative cells, the researchers say the next step is to look for ways to target the process to turn it off or on as needed to treat colorectal cancer and intestinal conditions that can lead to cancer.

“H3K36 methylation seems to be directly involved in differentiating the cells, but if you take it away, the cells revert to this regenerative stem cell state,” Dempsey says. “That regenerative state is important when you have injury and repair, but there also are certain colorectal cancers that have exactly this regenerative gene signature. Chronic colitis, inflammatory bowel disease, is a repetitive injury system, and leads to a higher risk of colorectal cancer. We think we have a mechanism that could be directly applied to those types of cancers, and that’s something we want to study.”

Outside of colon cancer, the methylation process also may have implications for resistance to chemotherapy and radiation, Dempsey says.

“When the cells switch into this regenerative stem cell state, they become more resistant to certain treatments, and that’s a problem,” he says. “If you have a patient who’s not a colon cancer patient but is undergoing chemotherapy or radiation therapy, one of the side effects of those therapies is that you get destruction of intestinal stem cells. In some patients, if it’s not dosed correctly, you can actually strip the whole lining of the intestine. If you could understand how to turn that state back on, you may be able to get the cells to be more protected.”

Future applications

Brumbaugh emphasizes that the recently published research is just the first step in understanding a process that could have a significant role in treating diseases in the future.

“As stem cell biologists, we want to understand the nuts and bolts of this process, because if you do, then you can manipulate it,” he says. “You might want to manipulate it for drug testing, for disease modeling — even if it’s not something where we have a direct therapy that we’re applying to patients, if we can understand how a disease works, then that provides options and opportunities to inform therapies.

“This would be far off in the future, but creating certain cell types for transplantation therapies is something that is very exciting in the stem cell arena,” he adds. “We’re not anywhere close to that, but if you understand how to manipulate the process, you can start thinking about these types of things.”