At the heart of the finding are enzymes called histone demethylases, whose task is to regulate the structure of chromatin, i.e. DNA and the attached proteins. The researchers demonstrated that the lack of oxygen prevents certain histone demethylases from working, as a result of which cells are unable to differentiate.
This new finding can be utilised in the development of novel cancer drugs. Cancer cells are typically undifferentiated, and chromatin abnormalities have been found in many cancers.
“Oxygen levels are often low in tumour tissues because of their rapid growth and inadequate vascularity, and, in addition, histone demethylases in many cancer cells are either mutated or missing altogether,” says MD, PhD Tuomas Laukka, who studied the subject in his doctoral dissertation.
It has been known that the lack of oxygen stops the differentiation of cells. A good example of this are stem cells, which are undifferentiated cells typically located in the most oxygen-poor ‘niches’ of the human body. Now, for the first time, researchers managed to demonstrate a direct link between oxygen content, histone demethylase activity, gene function and cell differentiation.
“For the first time, we showed that the amount of oxygen has a direct effect on histone demethylase activity. This effect was previously believed to be indirect,” Professor Peppi Karppinen from the University of Oulu says.
According to Karppinen, this finding will shape the perceptions of how the body senses oxygen. Through evolution, animals have developed an oxygen sensing method with a protein named HIF at the centre. It is activated when the blood oxygen level drops. However, this system does not exist in plants. Instead, they have histone demethylases. It is possible that histone demethylases are an earlier method of oxygen sensing in living organisms, preceding the HIF proteins.
Next, the researchers intend to take a closer look at why some histone demethylases are more dependent on oxygen than others.
Karppinen, who uses the name Koivunen in scientific articles, and her research team have conducted pioneering research into oxygen sensors in the body and pharmaceutical development for almost 20 years.
The published study is based on extensive collaboration between the University of Oulu and Harvard Medical School in the USA. In addition to Karppinen and Laukka, the key researcher from the University of Oulu was post-doctoral researcher Matti Myllykoski.
In Finland, this research has been funded by, for instance, the Academy of Finland, Jane and Aatos Erkko Foundation, Sigrid Juselius Foundation and Cancer Society of Finland.
Professor Peppi Karppinen (Koivunen)
Faculty of Biochemistry and Molecular Medicine, University of Oulu
Tel. +358 (0) 294 485822
Peppi Karppinen’s researcher profile
Article: Chakraborty et al. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate, Science, Mar 15 2019.
Last updated: 14.3.2019