Noncoding DNA regulates embryonic heart development in mice

A sequence of noncoding DNA has been shown to regulate a gene crucial for embryonic limb and heart development in mice.

An international group of scientists used a mouse model to investigate a noncoding DNA sequence next to the gene Shox2. This gene is known to be necessary for limb and cardiac development in both humans and mice. The team found that this region of noncoding DNA regulates the activity of Shox2. Removal of this noncoding DNA sequence in mice led to lethal heart defects and limb abnormalities, due to reduced Shox2 expression.

The sinoatrial node is an important region in the heart, responsible for generating electrical signals which initiate each heartbeat. 'Shox2 plays a key role in the formation of the sinoatrial node,' said Professor Marco Osterwalder from the Department for Biomedical Research at the University of Bern, Switzerland, and co-corresponding author of this study. Professor Osterwalder continued, 'We will use the findings of our study to determine how the development of the sinoatrial node is anchored within the genome'.

Earlier research had demonstrated the importance of Shox1 during development. Mutations within Shox1 and its adjacent noncoding region are associated with cardiac arrhythmias in humans. However, the exact mechanism by which Shox1 is regulated during development has remained unknown.

This study, published in Nature Communications, found 15 different regulatory regions, called enhancers, within the noncoding DNA sequence adjacent to Shox1. These enhancers work together to control when, and where, the Shox1 gene is active during embryonic development.

Professor Osterwalder said that this research not only identified the function of a novel noncoding region in the genome, but also 'shows how complex the mechanisms underlying the regulation of developmental genes are'. He added, 'These new findings can help us to better understand how enhancers work and how individual genes are active simultaneously in different cell types and tissues of the embryo.'

Historically, noncoding regions of DNA were described as 'junk DNA', as they do not code for any proteins. Research into noncoding regions of the genome, such as enhancers, is still emerging, with much left to uncover about their regulatory functions. Enhancers are short regions of DNA that can bind to transcription factors, allowing them to transcribe genes nearby. This work underlines the regulatory importance of noncoding DNA regions, particularly during development.

The researchers believe that there are additional enhancers located within this noncoding region which are yet to be identified. It is possible these enhancers may also play a role in heart development. In the future, they aim to explore how all these enhancers interact, not only with Shox1 and other genes, but also with each other. This will allow the team to unravel the intricate gene regulatory landscape involved in embryonic heart development.