SOX9 gene involved in scar formation after myocardial infarction

Grégory Lacraz from the Van Rooij group, together with other researchers, has identified a gene that is important for scar formation after myocardial infarction. They published an article about this in the scientific journal Circulation.

Research on myocardial infarction
During myocardial infarction, commonly known as a heart attack, part of the heart no longer receives any oxygen. This results in the loss of muscle cells, that are important for the pumping of blood through the body. These cells are replaced by a scar, which is made up of fibers that are much less elastic than the original muscle cells. This further impairs the ability of the heart to pump blood. The Van Rooij lab studies, among others, how the heart reacts to an infarction. They are mainly interested in the activity of genes; which genes become (more) active after an infarction, and which genes become less active. This is studied in mouse hearts, because they are similar to human hearts. Their aim is to gain more insight in the responses of the heart to ischemic injury, which may ultimately enable us to change these responses and for instance decrease scar formation.

Previous research on gene activity
In the past, researchers have studied which genes become more and less active after myocardial infarction. These researchers studied the activity of genes in the whole infarction area at once, and compared this to gene activity in healthy heart tissue. However, heart tissue is made up of many different cells and we know that there are many different responses to myocardial infarction. Furthermore, the response differs between the center of the infarction area, where there is no oxygen at all, and the edge of the infarction area that still receives some oxygen. By looking at the entire infarction area at once the researchers gained global knowledge into processes that take place after myocardial infarction, but specific information in which processes occur where in the infarction area was lost.

Differences within the infarction area
To gain insight in the specific processes and the activity of genes in the different locations in the infarction area, the Van Rooij group utilized a technique that has recently been developed at the Hubrecht Institute: Tomo-seq. They isolated a piece of the mouse heart that contained both infarcted and healthy heart tissue and sliced it into very thin slices. This resulted in slices from very deep in the infarction area to slices in the healthy tissue. They studied the gene activity in all these slices and gained more insight in gene activity differences within the infarction area.

An important gene for scar formation in the heart
Using this technique, the Van Rooij group has identified a gene, SOX9, with a changed activity in the infarction area compared to the healthy heart tissue. This gene turned out to be involved in scar formation in the heart. The protein that this gene encodes is a so-called transcription factor. A transcription factor can bind to the DNA and thereby activate other genes. Therefore, it is a kind of master regulator that can regulate various processes. The researchers have also found multiple genes that have a similarly changed activity as SOX9, which indicates that SOX9 regulates these genes.

Less active SOX9 results in diminished scar formation
Subsequently they studied SOX9 activity in human heart tissue after a myocardial infarction. The activity of SOX9 in these tissue samples was comparable to the activity in the mouse. In addition, they showed that less SOX9 activity in the mouse results in diminished scar formation after ischemic injury. This means that changing the activity of this gene can influence the whole process of scar formation. Further research is needed, but in the future this gene might be a target for the development of treatment after myocardial infarction in humans.

Prof. Dr. Eva van Rooij is group leader at the Hubrecht Institute Utrecht (KNAW) in Utrecht and professor of Molecular Cardiology at the University Medical Center Utrecht and Utrecht University.

Tomo-seq Identifies SOX9 as a Key Regulator of Cardiac Fibrosis During Ischemic Injury
Circulation 2017