Reprogramming embryonic stem cells into cardiomyocytes, or heart muscle cells, has huge potential for treating congenital heart disease, which affects up to one per cent of babies born in the UK.
Insights by scientists at the Francis Crick Institute (led by Dr Tim Mohun) into two proteins that are essential for heart development have allowed the scientists to develop a model to explain what happens when cardiomyocytes develop.
The two proteins, called NKX2-5 and MEIS1, are transcription factors, which means that their role is to bind to particular DNA sequences and control the activity of genes, each in their own way.
Dr Laurent Dupays of the Crick explained: "NKX2-5 and MEIS1 are essential for the development and normal physiology of the adult heart in vertebrates (animals with backbones), including humans. Mutations in NKX2.5 in humans have been suggested as the underlying cause of a variety of congenital heart diseases and MEIS1 has been identified as a cause of human cardiac arrhythmias."
The scientists studied mouse heart DNA to find out which genes the two proteins interact with in developing heart cells, and how they do so. They identified a set of genes in which the two proteins compete to bind, only one of the proteins binding the genes at any time.
They also found that as they develop, a crucial population of heart cells first experience high levels of MEIS1 and then increasing levels of NKX2-5. As a result, the genes switched from first being regulated by MEIS1 protein to then being regulated by NKX2-5 protein. This provides a simple way to explain how some genes are regulated in both space and time as the heart develops.
Dr Mohun explained: "Together, our study suggests a model to better explain the transcriptional program that takes place during heart cell development.
"These insights will be valuable for designing strategies to reprogramme embryonic stem cells into functional cardiomyocytes - cells that could transform our ability to treat patients whose hearts are damaged."
The paper, Sequential binding of MEIS1 and NKX2-5 on the Popdc2 gene: a mechanism for spatio-temporal regulation of enhancers during cardiac differentiation, is published in Cell Reports.
