All the cells in an organism have to adapt to changing requirements as they develop and grow - including muscle cells in the heart. Crucial to this process are the cells’ growth in size and epigenetic factors that play a role in modulating the expression of various genes. The role of epigenetics in cancer development has been the focus of research for quite some time. The question is, what role do epigenetic factors play in the development of the heart? Prof. Dr. Lutz Hein from the Institute of Pharmacology and Toxicology at the University of Freiburg studies the maturation of cardiac muscle cells and the epigenetic programmes involved. One of his goals is to better understand cardiac diseases.
The heart is the first organ to form in the growing embryo. It beats continuously from as early as the fifth week of pregnancy until death to supply the body with oxygen and nutrients. The relatively large muscle cells of the heart develop from precursor cells that initially, as the heart grows rapidly, still have the ability to divide. However, shortly after birth, most heart muscle cells lose this ability and have to adapt differently to changing physiological conditions. This means that heart muscle cells lose an important repair mechanism that cells in other body tissues maintain for life. "After a heart attack, only a few heart cells are able to regenerate through cell division," explains Prof. Dr. Lutz Hein from the University of Freiburg. “Following disease, most of the heart cells have to find other ways to adapt to changing conditions and repair damage. Conceptually, this is a particular challenge as damage needs to be repaired while the heart is beating. “Although many more people survive myocardial infarction than was previously the case due to progress in medical technology, it leaves many survivors with chronic heart failure or high blood pressure. Hein believes that therapeutic improvements can only be achieved on the basis of fundamental insights into how cardiac muscle cells work and how they regenerate.
In the mouse model, Hein was able to switch off two enzymes that mediate the methylation of the genes coding for foetal proteins and found that two cardiac muscle protein isoforms were in fact present when methylation was prevented. “When methylation is prevented, some of the foetal cardiac muscle genes remain functional. With this model, we showed that in foetal proteins there was a direct link between methylation and gene expression.” Hein is still looking for the molecular factors that remove methyl groups from genes after birth, activating the adult genes.
It is noteworthy that the epigenetic programme also changes in the cardiac muscle cells of diseased hearts, in the case of chronic heart failure, for example. The expression of proteins that have not reached full power and are thus involved in the reduced performance of the organ is a marker of chronic heart failure. Hein calls this a return to the foetal gene programme, but he is still looking for explanations as to why it occurs. Maybe being able to form other protein isoforms under stress benefits cardiac muscle cells. Rather than removing methyl groups, cells up- or downregulate a protein that recognizes the methyl groups, thereby affecting the expression of the relevant genes. “This allows the cells to temporarily fine-tune gene expression, while the long-term switch, i.e. methylation, remains,” said Hein. In mouse models used to examine the protein MeCP2, Hein and his team were able to substantiate the plastic situation that they had assumed existed.
Chronic heart failure is characterized by a huge increase in cell size, similar to that which is observed in newborns. The diseased heart needs to cope somehow with increased stress and does so getting bigger. If the heart recovers, these changes can be reversed. The researchers are already thinking about ways to diagnose heart disease very early on. They have developed a method to separate cardiac muscle cells from tiny frozen tissue samples that uses probes and antibodies to map the epigenome of cardiac muscle cells. The researchers want to refine the method in order to conduct epigenetic analysis on miniscule tissue biopsies. “I am sure that this will keep us busy for quite some time to come,” says Hein.
Further information:Prof. Dr. Lutz HeinInstitute of Pharmacology and ToxicologyUniversity of FreiburgAlbertstr. 2579104 FreiburgTel.: +49 (0)761 / 203 - 5313Fax: +49 (0)761/ 203 - 5318E-mail: lutz.hein(at)pharmakol.uni-freiburg.de