Epigenetic changes help cells adapt to low oxygen levels, study reveals

Researchers at Karolinska Institutet have discovered how cells can adjust the activity of their genes to survive when oxygen is low. The study, published in Natural cellular biologyreveals that cells use a previously unknown mechanism to control which proteins are produced and at what rate.

When cells suffer from a lack of oxygen, such as in the case of a tumor or after an injury, they must quickly adapt to survive. In this new study, researchers explored how this adaptation works at the molecular level. By studying both breast cancer cells and human stem cells, they discovered that the cells change where genes are read from, which affects how efficiently proteins are made.

“We found that cells in hypoxia often use alternative start sites to regulate genes, which changes the characteristics of the so-called 5′UTR sequence of mRNA,” explains Kathleen Watt, postdoctoral researcher at the Department of Oncology-Pathology at Karolinska Institutet and first author of the study.

This sequence acts as a “momentum” before the actual protein begins to form. The characteristics of these sequences control how efficiently the cell can produce proteins. Researchers have found that under low-oxygen conditions, cells often choose different versions of the 5’UTR, allowing certain important proteins to be made more efficiently.

One example is the enzyme PDK1, which helps the cell switch its energy production from an oxygen-dependent process to one operating without oxygen, called glycolysis. This is a key survival strategy for cells in stressful environments.

Epigenetics controls change

The researchers also showed that this change is controlled by epigenetic changes – chemical changes in the way DNA is packaged that affect active genes. A specific modification called H3K4me3 was found to play a crucial role. By influencing this change with drugs, researchers were able to cause cells to change the sites of origin of their genes, even without changing oxygen levels.

“This suggests that epigenetic changes are not just a consequence of hypoxia, but an active part of the cell’s adaptation strategy,” explains Krzysztof Szkop, a postdoctoral researcher in the same department and co-first author of the study.

The study provides new insights into how cells regulate protein production under stress and could be important for future cancer research, since tumor cells often live in low-oxygen environments.

“This study is the result of a fantastic collaborative effort between our group here at Karolinska Institutet and Dr. Lynne-Marie Postovit’s group at Queen’s University, as well as our other colleagues in Canada,” says Ola Larsson, principal investigator, also in the Department of Oncology-Pathology and co-corresponding author of the study.