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Title

UCLA study challenges common theories on how heart disease develops

Health News

Date
09/06/2017
Article

Heart failure is linked to modifications in how DNA is packaged within heart cells, UCLA researchers have found.

Their findings, published in the journal Circulation, represent a new way to think about both the development of heart disease and its treatment, said Thomas Vondriska, a UCLA professor of anesthesiology, medicine and physiology and the study’s senior investigator.

Heart disease has long been thought to be caused by one or a small number of genes that are not acting as they should, so treatment is often based on either restoring or eliminating the function of those genes. But in this study of mice models of heart failure, researchers found that a change in how DNA is packaged can alter the functioning of more than half of the genes in the genome.

DNA, which in humans is six feet long if stretched into a long thread, needs to be compressed into a tiny structure, called chromatin, to fit inside a cell’s nucleus. The ribbon of DNA is wound around proteins known as histones, which, along with other molecules, allow proper storage and accessibility of the genetic material.

Disabling a single protein that works like mortar in shaping the chromatin changed the activity of more than 3,000 genes in the spooled strand of DNA within mouse heart cells. Genes that needed to be near each other or touching in order to work were slightly displaced in the altered chromatin, and thus malfunctioned.

“This study tells us that simply changing the way genes are packed together — even by a little bit — can have a widespread effect on the functioning of cells,” Vondriska said. This observation suggests treatments that restore the right arrangement of the chromatin might be able to restore proper genome-wide functioning, he said.

“This is startling and quite exciting because it allows us to challenge assumptions about how cells work and about what causes disease — in this case, heart failure, which affects over 5 million Americans,” Vondriska said.

The protein that investigators deleted is called CTCF, which is one of a number of chromatin structural proteins in cardio myocytes (heart cells), as well as in cells of other organs and tissues. 

The study had two phases. The first was to use a technique known as “chromatin conformation capture” to map the 3-D shape of cardio myocte chromatin in healthy mice — the first time this has been done.  A genome-wide measurement of RNA expression was also conducted to assess the activity of each gene in the genome.

The “atlas” that resulted showed a structure that resembled a head of broccoli — different length loops of DNA, wrapped around histones, which allowed genes to work with each other.

“We knew precisely which genes were close enough to be co-regulated. They worked together as a team,” said Manuel Rosa-Garrido, the study’s first author and a member of Vondriska’s team.

“The second phase was to examine two different mouse models of heart failure, one of which was caused by high blood pressure and the other that resulted from deletion of the chromatin structural protein CTCF,” said co-author Douglas Chapski, a graduate student in the Vondriska lab.

Deleting CTCF in the mice didn’t fundamentally alter the structure of chromatin, but shortened some loops of DNA and lengthened others, similar to what was seen in the model that mimics high blood pressure. These changes affected a substantial portion of the genome. “The changes in structure were very specific — the chromatin still looked like broccoli overall— but the effect on how the heart cells functioned was dramatic,” Rosa-Garrido said.

Although the study was conducted in mice, Vondriska said he expects to find the same phenomenon in humans with heart failure. He added that different proteins linked to chromatin structure may also be involved in heart failure as well as in other common disorders.

“This is a basic science investigation, so the insights we have obtained reveal new principles about the fundamental inner workings of the heart cells,” Vondriska said. “In the future, however, the idea we want to test is whether delivering an enzyme that resets the chromatin structure will restore health. The hope is that what we observe in terms of global chromatin structure may turn out to be true for disorders in other organs.”

The study’s other authors are UCLA researchers Todd Kimball, Elaheh Karbassi, Emma Monte, Tsai-Ting Shih, Elizabeth Soehalim, Shuxun Ren, Yibin Wang, David Liem, Peipei Ping and Matteo Pellegrini; Enrique Balderas, from the University of Utah; Anthony Schmitt and Bing Ren, from UC San Diego; and Niels Galjart, from Erasmus Medical Center in the Netherlands.

The study received support from the National Institutes of Health and the UCLA cardiovascular research theme.

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