DNA exists in every cell in the body, but it is packaged differently in every type of cell or tissue. folded DNA is called chromatinand its configuration helps to regulate gene expression. It does this by allowing transcription to occur along certain stretches of DNA as needed during its life cycle. Thus, cells must be able to control chromatin structure and remodeling capabilities in order to function properly.
However, disturbances in the microenvironment of the cell, as in disease, can disrupt the mechanisms that control chromatin. In addition, long-term disturbances can eventually cause altered cells to stop responding to environmental cues, even after conditions return to normal.
To better understand why this is happening, researchers at the University of Pennsylvania’s Pearlman School of Medicine (UPENN) set out to investigate the cells of degenerating connective tissue due to tendinosis. In particular, they were interested in how environmental changes caused by disease affect the spatial organization of chromatin. Their findings were published in the August 22 issue of the journal. natural biomedical engineering.
Epigenetic processes such as DNA methylation, histone methylation, and histone acetylation control the state of compaction or accessibility of chromatin. Relaxed or open chromatin provides access for transcription factors to DNA, while densely packed chromatin closes certain parts of the DNA.
In previous articles, we have discussed the importance of chromatin availability during early heart development and how chromatin remodeling determines the fate of bone marrow cells during aging. This article discusses the physical structure of chromatin and how disease affects its dynamic response to external stimuli.
Using the latest ultra-high-resolution imaging techniques, the team observed human models of tendon cells (tenocytes) and mesenchymal stromal cells (MSCs), which act similarly to stem cells.
When the environment was mimicked that of a weakened or degenerative tendon through chemical and mechanical changes, the team found chromatin misorganization within the cells. After the researchers returned the environment to normal, they also saw that the chromatin remained out of order and that the cell could no longer respond properly.
In contrast, healthy cells tested responded well to the same chemical and mechanical stimuli, indicating that diseased cells may have either forgotten or failed to find the exact information they need to reorganize properly.
The researchers suggest that these changes prevent damaged cells from healing properly and may benefit from targeted therapies.
“While we found that cells in a diseased microenvironment lose their epigenetic memory, these results also suggest that epigenetic treatments, such as small molecule drugs, can restore healthy genome organization and may prove to be an effective treatment for conditions that affect dense tissues. This is something we plan to test and test,” said Melike Lakadamyali, PhD, associate professor of physiology at PENN and senior author.
Interestingly, the observations described in this study led to a new theory based on two different fields of science – physics and biology.
“We have been able to explain the role of mechanical forces in the three-dimensional organization of chromatin by developing a theory that combines fundamental thermodynamic principles (physics) with the kinetics of epigenetic regulation (biology),” said Vivek Shenoy, Ph.D., co-author. author and director of the Pennsylvania Center for Engineering and Mechanobiology, and Eduardo D. Glandt Distinguished Professor, President of UPENN Engineering.
Having already received appropriate grants, the researchers plan to study how disease-damaged genomes affect cartilage and meniscus cells. In addition, they will study whether aging has a similar result.
“Once we understand these and the specific cellular processes that cause them,” said Robert L. Mauk, MD, professor of orthopedic surgery and director of the UPENN McKay Orthopedic Research Laboratory. “We can use small molecule drugs as a lock-pick to either try to prevent this or reverse the process.”
Source: Su-Jin Ho et al. Aberrant chromatin reorganization in affected fibrous connective tissue cells in response to altered chemical-mechanical signals. natural biomedical engineeringAugust 2022
Link: Closed Library: Disease causes cells to misorder their DNA. University of Pennsylvania School of Medicine. August 22, 2022