Remember when we thought most of the human genome was "junk" DNA? Because when scientists first sequenced it, they found less than 3% of the DNA was for coding proteins, the building blocks of life. Since then, they have been discovering some surprising things about non-coding DNA. In a new study published this week, a team describes how some of it codes for a genetic snippet of "long non-coding RNA" (or lncRNA) that controls the destiny of stem cells that differentiate into various types of heart cell. Without this vital piece of genetic code it seems hearts can't be made at all.

In a study reported online in the journal Cell on 24 January, biologists from Massachusetts Institute of Technology (MIT) describe how they identified a critical role for a lncRNA they dubbed "Braveheart".

Braveheart Controls Transformation of Stem Cells Into Heart Cells

In recent years, scientists have discovered areas of DNA that do not give instructions on how to make proteins, are codes for making lncRNA molecules that help to control when genes are switched on and off inside cells.

But while thousands of these genetic snippets have been found, very little is known about their specific roles.

The MIT team suggests the snippet they have identified, Braveheart, controls the transformation of stem cells into heart cells when embryonic stem cells are differentiating.

Potential New Avenue for Regenerative Drug Development

Although they made their discovery using mouse stem cells, they believe the same thing happens in humans.

If that turns out to be the case, then studying lncRNAs could lead to a new way of developing regenerative drugs to treat hearts damaged through aging or cardiovascular disease.

Co-lead author Carla Klattenhoff, a postdoc in MIT's Department of Biology, says in a statement:

"It opens a new door to what we could do, and how we could use lncRNAs to induce specific cell types, that's been completely unexplored."

Braveheart Essential for Unblocking Master Gene for Heart Cell Differentiation

The team decided to investigate Braveheart because they found lots of it in embryonic stem cells and in differentiating heart cells.

In their study they show how mouse embryonic stem cells that don't have enough Braveheart lncRNA fail to develop any of the three major types of cell of the cardiovascular system: cardiomyocytes (which make cardiac muscle), smooth muscle cells and endothelial cells.

They also found that without Braveheart, MesP1, the master gene that regulates heart-cell differentiation in vertebrate animals, doesn't work. When it works, MesP1 kicks off a cascade of hundreds of genes that are essential for heart development.

It appears that Braveheart controls the cascade by influencing the PRC2 protein complex, which normally sits on top of DNA, blocking MesP1 and other genes that are essential for developing heart cells.

When Braveheart is present,the MesP1 network kicks off the heart development process.

What Next?

Ramin Shiekhattar is a professor of gene regulation and expression at the Wistar Institute in Philadelphia, and was not part of the study team. He says:

"This paper is definitely a first step toward what we need to do, which is understand in a more fundamental way the biological role of these noncoding RNAs."

He says the next thing that needs to happen is to decipher the detailed mechanisms of Braveheart, and test what happens when it is knocked out in live mice.

The MIT team suggests noncoding RNAs could explain why the human heart is more complex than say the heart of a fly. Because many of the genes for coding heart proteins are the same in the two species.

Co-lead author Johanna Scheuermann, also a postdoc in MIT's Department of Biology, says:

"We think that the added complexity may come from the non-coding portion of the genome, and we think lncRNAs are involved."

The team is now searching for other noncoding RNAs that play a role in heart development in mice, and for the human equivalent.

They haven't yet identified the human analog of Braveheart. This is not surprising, says Klattenhoff, given that long noncoding RNAs tend to evolved more rapidly than genes that code for proteins.

But the team expects eventually to identify many new noncoding RNAs that are essential for human heart development, and perhaps also, mutations that influence the development of cardiovascular diseases.

Funds from the Damon Runyon Cancer Research Foundation, the National Institutes of Health, the Watkins Cardiovascular Leadership Award, the Life Sciences Research Foundation, the European Molecular Biology Organization, and the Richard and Susan Smith Family Foundation helped finance the study.

In September 2012, Nature, Science, and other journals published a staggering collection of over 30 papers firmly rejecting the idea of "junk DNA".

Written by Catharine Paddock PhD