DNA Blueprint Maps How A Heart Becomes A Heart

Date: Sep-17-2012Using stem cell technology, next-generation DNA sequencing and computer tools, researchers at the Gladstone Institutes in California, and other
academic centers, have mapped how a heart becomes a heart, revealing a genomic and epigenomic blueprint for the precise order and timing of hundreds of
"genetic switches" from embryonic stem cell stage to fully functioning heart.

The researchers write about their work in the 13 September online issue of Cell.

The findings bring hope of new treatments for people born with life-threatening heart defects like irregular heart beat (arrhythmia) and hole in the
heart (ventricular septal defect).

Senior investigator Benoit Bruneau, associate director of cardiovascular research at Gladstone, an independent, nonprofit biomedical research group, tells the
press in a statement:

"Congenital heart defects are the most common type of birth defects -- affecting more than 35,000 newborn babies in the United States each year."

"But how these defects develop at the genetic level has been difficult to pinpoint because research has focused on a small set of genes. Here, we approach heart
formation with a wide-angle lens by looking at the entirety of the genetic material that gives heart cells their unique identity," he explains.
From Mountains of Data to Readable Blueprint
For their study, the team took embryonic stem cells from mice, put them in a culture resembling embryonic development, and reprogrammed them to form
beating heart cells.

This completed part of the process: because as scientists are increasingly discovering, it is not just having these cells that decides how an organ becomes an
organ, but also having a detailed control map of how the genes switch on and off during various stages of development: the epigenomic signatures.

For this part of the experiment they extracted DNA from developing and mature heart cells, because they contain the epigenetic signatures written in the DNA.
They did this using CHIP-seq, an advanced gene-sequencing tool.

However, even this was not enough to give them a full, working, blueprint, as Jeffrey Alexander, co-lead author and graduate of Gladstone and University of
California, San Francisco (UCSF), with which Gladstone is affiliated, explains:

" ... simply finding these signatures was only half the battle -- we next had to decipher which aspects of heart formation they encoded."

"To do that, we harnessed the computing power of the Gladstone Bioinformatics Core. This allowed us to take the mountains of data collected from gene
sequencing and organize it into a readable, meaningful blueprint for how a heart becomes a heart," he added.
Some Unexpected Discoveries
The researchers made some surprising discoveries: not only did they find whole groups of new genes involved in heart formation, but they refined how they
interact with previously known genes.

They also found groups of genes in heart cells seem to work in concert, switching on and off together at precise stages of embryonic development.
Implications
The researchers suggest their discoveries have important implications for human heart health: by piecing together a detailed map of how genes control the heart,
they believe they can also discover how disease disrupts this finely controlled process.

They say with a better understanding of how complex genetic and epigenetic patterns are precisely regulated, developers are better equipped to find
treatments that prevent, intervene, or oppose disruptions to these patterns by disease, for instance to help children with congenital heart defects.

Bruneau, who is also a professor of pediatrics at UCSF, says they now want to look at the DNA of patients living with congenital heart disease, in the hope they
can "pinpoint the specific genetic disruption that caused their heart defect."

"Once we identify that disruption, we can begin exploring ways to restore normal gene function during early heart formation -- and reduce the number of babies
born with debilitating, and sometimes fatal, congenital heart defects," he adds.

Written by Catharine Paddock PhD

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