Scientists get the upperhand in biological pathway that leads to heart formation

The DNA sequence they studied -- which they named Upperhand (Uph) -- is located just before a gene called Hand2, whichcontrols the development of the heart as it grows in the womb.

"These findings uncover a new and unexpected step in the control of heart formation whereby one gene, Upperhand, regulates the expression of the neighboring gene, Hand2, by an unusual mechanism," said Dr. Eric Olson, Director of the Hamon Center for Regenerative Science and Medicine, and Chairman of Molecular Biology.

Upperhand works something like a safe, which holds the controls for Hand2 locked inside it.

Upperhand has to be opened up first for the Hand2 controls to be exposed. That ultimately allows Hand2 to set in motion a whole sequence of events that are crucial to formation of the heart.

Upperhand also may help explain the mystery behind why some DNA sequences don't serve as templates for synthesizing proteins like other DNA sequences. Those that don't are called non-coding DNA and scientists have been pondering what they do and how they work.

"These non-coding sequences are the mysterious "dark matter" of the genome," said Dr. Olson, who holds the Robert A. Welch Distinguished Chair in Science, the Pogue Distinguished Chair in Research on Cardiac Birth Defects, and the Annie and Willie Nelson Professorship in Stem Cell Research.

Upperhand is one such "non-coding" DNA that doesn't serve as the template for a protein.

"Why would it be located before Hand2, we wondered? What we learned is that the [controls] for Hand2 just happen to be trapped inside Upperhand," Dr. Olson said. "This is probably a general mechanism for the control of many genes that are important in development, because so many cardiac control genes are adjacent to non-coding RNAs and nobody ever understood why that is."