Scientists at the Gladstone Institutes have discovered how a group of transcription factors interact during embryonic development to form a healthy heart. Their findings deepen our understanding of heart formation and may lead to new treatments for cardiovascular disease.
The study, published today in the journal Cell, describes how cardiac transcription factors work together. Transcription factors are proteins that control gene expression by binding to specific DNA sequences and recruiting other proteins that convert genetic instructions into functional proteins.
Each organ relies on its own set of transcription factors to coordinate development, and these factors often interact directly to drive precise biological events. These interactions are essential for building healthy tissues and organs, but scientists still don’t fully understand how they work.
For the heart, researchers already know a group of transcription factors critical for cardiac development, and mutations in these factors can disrupt heart formation and cause defects in newborns. What remains unclear is how some of these factors interact to carry out their roles.
A cardiac love triangle
In this study, Gladstone scientists examined how three key cardiac transcription factors interact during heart development. They first used mouse embryos in their research. When they removed any one of the three, the embryos developed abnormal hearts. Removing two factors, NKX2.5 and TBX5, caused even more severe outcomes. In those cases the heart failed to form, and none of the embryos survived.
Next, the team studied how these transcription factors coordinate gene expression in cardiomyocytes made from mouse embryonic stem cells lacking two of those factors. Compared to normal heart cells, these altered cardiomyocytes began beating at the wrong times.
A closer look showed that the three transcription factors cluster in the same regions as embryonic stem cells transition into cardiomyocytes. Each transcription factor needed the others to bind its DNA targets. When one factor was missing and the “love triangle” broke, the remaining factors became disorganized. In those cases they binded random DNA sequences and activating genes that should have stayed off.
First author on the study, Luis Luna-Zurita, explained the importance of maintaining this cardiac love triangle in a Gladstone Press Release:
“Transcription factors have to stick together, or else the other one goes and gets into trouble. Not only are these transcription factors vital for turning on certain genes, but their interaction is important to keep each other from going to the wrong place and turning on a set of genes that doesn’t belong in a heart cell.”
Crystal structure tells all
The final part of the study showed that two of these factors, NKX2.5 and TBX5, directly interact and physically touch each other when they bind their DNA targets. Working with collaborators at the European Molecular Biology Laboratory (EMBL) in Germany, the team developed protein crystal structures to model how these transcription factors bind DNA at the molecular level.
Co‑author and EMBL scientist Christoph Muller explained his findings:
“The crystal structure critically shows the interaction between two of the transcription factors and how they influence one another’s binding to a specific stretch of DNA. Our detailed structural analysis revealed a direct physical connection between TBX5 and NKX2-5 and demonstrated that DNA plays an active role in mediating the interaction between the two proteins.”
Big picture
While this study falls under discovery research, its findings deepen our understanding of how a healthy heart forms and shed light on what goes wrong in patients or newborns with heart disease.
Senior author Benoit Bruneau, a Gladstone professor, explained the potential biomedical applications of this work for treating human disease:
“Gene mutations that cause congenital heart disease reduce these transcription factors by half, and we’ve shown that their dosage determines which genes a cell turns on or off. Other genetic variants that cause defects such as arrhythmias also disrupt how these factors function. The more we understand these transcription factors, the closer we get to developing treatments for heart disease. Our colleagues at Gladstone are using this knowledge to search for small molecules that can influence gene regulation and reverse some of the problems caused by the loss of these factors.”
These studies used mouse embryos and mouse embryonic stem cells. Future work will need to show whether this cardiac interaction network functions the same way in human heart cells.
Related Links: