The main function of cardiomyocytes, the cells of the heart muscle, is to pump blood to other organs in the body. However, they can also carry genetic instructions and function like a nerve cell, liver cell, intestinal cell, or any other type of cell in the body.

Dr. Deepak Srivastava says, “The moment the fetal heart begins to develop, master switch proteins, called transcription factors, act as the first mosaic in an extremely complex domino pattern and trigger a chain of events that lead to the activation of specific genes of the heart muscle in cardiomyocytes, as well as the silencing of genes important for the development of other types of cells “.

The process creates functional hearts in more than 355,000 babies born every day. However, it is not entirely flawless and often leads to heart defects. It has been observed that almost 1% of babies are born with heart defects.

Scientists at the Gladstone Institutes have studied a family with a history of heart defects to understand how the genetic network works incorrectly that can cause heart defects and even heart disease later in life. In 2003, the family consulted Deepak Srivastava, director of the Gladstone Cardiovascular Institute. His problem was critical and rare. Half of the children in the family were born with a hole in the wall between the two chambers of the heart.

After analysis, Gladstone’s team found that all of the children, born with a hole in the wall, had a mutation in their GATA4 gene. It leads to a heart transcription factor protein. All of the children developed heart disease, such as a poor heartbeat, after seven years. However, although the two heart conditions were not directly related, Srivastava’s team believed that the GATA4 mutation was responsible for both.

The team was eager to figure out how the GATA4 mutation could lead to the two heart problems. In the process, they collected skin samples from the children and created cardiomyocytes. They also collected samples from their healthy siblings, so they could conduct comparative analysis in the laboratory. All tests showed that cells with the GATA4 mutation demonstrate weakened function compared to healthy cells.

The team also examined how the GATA4 protein interacted with the TBX5 protein. Both proteins are seen to control genes by interacting and binding to DNA. The study showed that in cells with damaged GATA4, the TBX5 protein did not bind well to DNA. The team also found that the GATA4 mutation creates an obstacle in the interaction with TBX5, whereby non-specific genes in the heart cause further disturbances in the development of cardiomyocytes.

Deepak Srivastava stated: “By studying the patients’ heart cells in a dish, we were able to find out why their hearts were not beating correctly. Investigation of their genetic mutation revealed an entire network of genes that failed, first causing septal [heart wall] defects and then heart muscle dysfunction. “

GATA4 and TBX5 are the first dominoes to belong to an intricate network of genes. So thinking about a treatment with these proteins would not be practical. Also, if they are blocked, they could lead to a worse situation. Therefore, finding a drug that affects a particular set of GATA4 / TBX5 actions could lead to a new therapy to cure heart disease.

Yen-Sin Ang, the first author of the report, said: “It is surprising that by studying genes in a two-dimensional group of heart cells, we could discover information about a disease that affects a complicated three-dimensional organ. This conceptual framework could be used to study other diseases caused by mutations in proteins that serve as master regulators of entire gene networks. “