Diseased connective tissue cells alter the physical structure of their genomes

Researchers at Penn Medicine have found that when cells are impacted by the disease, the physical structure of their genome changes.

Imagine trying to complete a task and all the information needed is contained in a small number of library books. However, those books are dispersed among the other books on shelves across the entire structure. The work can be done very effectively only if there is access to that important information from the books.

This is the scenario that scientists at the Perelman School of Medicine at the University of Pennsylvania discovered when they analyzed the nucleus of cells inside connective tissues deteriorating as a result of tendinosis.

The reorganization of the genome, which is the sum of an organism’s DNA sequences, inside the cell’s nucleus as a result of disease-related changes in the settings that cells exist in altered how cells functioned and rendered them unable to correctly reorder their DNA information once more.

The results published in Nature Biomedical Engineering suggest the potential for novel therapies, such as small-molecule therapies, to introduce a kind of librarian who could bring order to the damaged cells.

This is really important because the research tells us, for the first time, that diseased connective tissue cells change the physical structure of their genomes and stop responding to normal physical cues from their environment. If we can figure out exactly why this happens, we might be able to ‘unlock’ the diseased state of these cells, and bring them back toward a healthy state.”

Su Chin Heo PhD, Study Lead Author and Assistant Professor, Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania

Since they alter cell activities and how a body works, “microscale” alterations in the settings that cells reside in have macro-level impacts. However, this dynamic is not entirely clear.

Heo and colleagues set out to investigate how the spatial organization of chromatin, the substance that makes up DNA and has been shown to vary depending on cell type, may be impacted by changes caused by disease. This was done in order to better understand how cells in degenerating connective tissue respond to changes in their physical environment.

The scientists did this by observing human cell models using the most recent super-resolution imaging techniques, particularly tenocytes (tendon cells responsible for maintaining the tissue's structure) and mesenchymal stromal cells (similar to stem cells, they can become a variety of cells needed to build or maintain tissue).

In these models, the researchers noticed that tenocytes’ chromatin was inappropriately rearranged as a result of chemical and mechanical alterations within settings that mimicked degenerating tendons. Even when the investigators gave these cells the right mechanical environment, they observed that the cells had lost their capacity to correctly re-organize their genome to return to a normal condition - the cells could no longer respond appropriately.

It appears that the diseased cells forgot what they were doing or were unable to obtain the necessary information in their crisis response because they did not react as well to the same chemical and mechanical cues that healthy cells did.

While we discovered that cells in diseased microenvironments lose their epigenetic memory, these results also suggest that epigenetic treatments—like small molecule medications—could restore healthy genome organization and may prove effective treatments in conditions affecting dense tissues. That’s something that we plan to follow up on and test.”

Melike Lakadamyali PhD, Study Senior Author and Associate Professor, Physiology, Perelman School of Medicine, University of Pennsylvania

An innovative idea that combined two distinct scientific fields was developed as a result of what was observed to occur.

Interestingly, we were able to explain the role of mechanical forces on the 3-D organization of chromatin by developing a theory that integrates fundamental thermodynamic principles (physics) with the kinetics of epigenetic regulation (biology).”

Vivek Shenoy PhD, Study Co-Author and Director, Penn Center for Engineering and Mechanobiology

Vivek Shenoy is also the Eduardo D. Glandt President’s Distinguished Professor in Penn Engineering.

The investigators already have funding to investigate whether disease-disrupted genomes have a comparable impact on meniscus and cartilage cells. They are also researching whether aging has a comparable impact.

“Once we understand these and the specific cellular processes that makes them happen – what locks the library door—we can use small molecule drugs as skeleton keys to either try to stop it from happening or reverse the process,” adds study co-senior-author Robert Mauck, PhD, a professor of Orthopedic Surgery and director of Penn’s McKay Orthopedic Research Laboratory.