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ADVANCE IN CHEMICAL EPIGENETICS

Researchers Write and Erase DNA Methylation with Light

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A man on the left and a woman and a man on the right in the lab wearing white coats. © TU Dortmund
Prof. Daniel Summerer, Dr. Shubhendu Palei and Jan Wolffgramm (from left) has achieved an important advance in chemical epigenetics.
Scientists at TU Dortmund University have achieved an important advance in the field of chemical epigenetics: In two studies, they describe for the first time how light can be used to directly switch the writing and erasure of DNA methylation. A central process in human biology, DNA methylation regulates, for example, the development of embryos and the onset of cancer. The research results have been published in two renowned scientific journals.

To understand what the researchers have achieved, one must first recall the basic biological principles: DNA methylation is a chemical modification of the basic building blocks of DNA – the hereditary substance of a cell. Through this modification, a cell can flexibly switch its genes on or off. It has long been known that abnormal or missing methylations of DNA building blocks can disturb cell growth and transform a healthy cell into a proliferating cancer cell. For this reason, scientists would like to find out exactly how this process takes place in the cell.

Methylation is “written” on DNA, or “erased” from it, by specific enzymes. Previously, however, it has not been possible to precisely switch the responsible enzymes directly in cells to investigate the subsequent processes in detail. Prof. Daniel Summerer’s research group in the Chemistry and Chemical Biology Department at TU Dortmund University has now been able to do this for the first time – with the help of light. This work could provide a foundation for new insights, never before possible, into the sequence and speed of the processes responsible for the changes cells undergo during embryonic development and the onset of cancer.

How light can be used in DNA methylation

Chemical biologists Dr. Shubhendu Palei and Jan Wolffgramm from the research group use light as a stimulus because it offers very high spatial and temporal resolution and, in addition, is non-invasive – a perfect fit for investigating local and rapid processes in intact cells and whole organisms. First they had to place particular artificial amino acids that can be cleaved by light at key sites on the enzyme. At specific points in time, they then were able to activate the enzymes with brief irradiation in the cells and observe what happens next. In this way, the team investigated the effect of various cancer-relevant mutations on the enzymes’ activity and obtained the first insights into which genes this activity switches on or off, in what sequence, and how strongly. In addition the team managed to develop programmable “writer enzymes” that can selectively methylate specific sequences in the genome, thus enabling the strength of this methylation to be precisely controlled through the duration of the light irradiation.

These studies, published in the Journal of the American Chemical Society and An­ge­wand­te Chemie, were conducted within the framework of the project EPICODE. For this project, starting in 2017, the European Research Council awarded Prof. Daniel Summerer an ERC Consolidator Grant of nearly two million euros. Other collaborators on these studies were Prof. Michal Schweiger’s epigenetics and tumor biology research group at the University of Cologne and Dr. Petra Janning of the Max Planck Institute for Molecular Physiology in Dortmund.

Links to the original publications:

Light-Activatable TET-Dioxygenases Reveal Dynamics of 5-Methylcytosine Oxidation and Transcriptome Reorganization

Light‐Activation of DNA‐Methyltransferases

 

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