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UTSW scientists get the upperhand in biological pathway that leads to heart formation

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Credit: UT Southwestern

DALLAS – Oct.26, 2016 – Researchers at UT Southwestern Medical Center's Hamon Center for Regenerative Science and Medicine have identified a pathway essential to heart formation and, in the process, unveiled a mechanism that may explain how some previously puzzling segments of the genome work.

The DNA sequence they studied – which they named Upperhand (Uph) – is located just before a gene called Hand2, which controls 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."

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The research, which appears online in Nature, was supported by grants from the National Institutes of Health, Foundation Leducq Networks of Excellence, Cancer Prevention and Research Institute of Texas, and the Robert A. Welch Foundation, as well as a pre-doctoral fellowship from the American Heart Association and a Muscular Dystrophy Association Development Grant.

Other UT Southwestern scientists who contributed to this research are Dr. Kelly M. Anderson, former graduate student; Dr. Douglas M. Anderson, former postdoctoral fellow; John McAnally, research scientist in Medicine; and Dr. Rhonda Bassel-Duby, Associate Director of the Hamon Center for Regenerative Science and Medicine and Professor of Molecular Biology.

UT Southwestern's Hamon Center for Regenerative Science and Medicine was made possible by a $10 million endowment gift from the Hamon Charitable Foundation, and was generously supported by the State of Texas in the 84th Legislative Session. The Center's goal is to understand the basic mechanisms for tissue and organ formation, and then to use that knowledge to regenerate, repair, and replace tissues damaged by aging and injury.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year.

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Cathy Frisinger
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