University of North Carolina scientists have created a new research tool, based on the fruit fly, to help crack the histone code. This research tool can be used to better understand the function of histone proteins, which play critical roles in the regulation of gene expression in animals and plants.

This work, published in the journal Developmental Cell, opens the door to experiments that are expected to uncover new biology important for a host of conditions, such as neurological diseases, diabetes, obesity, and especially cancer, which has become a hotbed of epigenetic research.

"People think cancer is a disease of uncontrolled proliferation, but that's just one aspect of it," said Robert Duronio, PhD, professor of biology and genetics and co-senior author. "Cancer is actually a disease of development in which the cells don't maintain their proper functions; they don't do what they're supposed to be doing." Somehow, the gene regulation responsible for proper cell development goes awry.

One aspect of gene regulation involves enzymes placing chemical tags or modifications on histone proteins -- which control a cell's access to the DNA sequences that make up a gene. Properly regulated access allows cells to develop, function, and proliferate normally. The chemical modification of histones is thought to be a form of epigenetic information -- information separate from our DNA -- that controls gene regulation. This idea is based on the study of the enzymes that chemically modify histones. However, there is a flaw in this argument.

"In complex organisms, such as fruit flies, mice, and humans, scientists have only been able to infer how these enzymes mechanistically accomplish their tasks," said Daniel McKay, PhD, assistant professor of genetics and biology and first author of the paper. "It's been technically impossible to directly study the role of histone modifications. Now, through our collaboration between UNC biologists, we've been able to develop a tool in fruit flies to directly test the function of histones independently of the enzymes that modify them."

This is crucial because therapies, such as cancer drugs, can target histones. With this new research tool, scientists will be able to better study thousands of enzyme-histone interactions important for human health.

"If you think of the genome as a recipe book, then you could say we've made it possible to know that there are hidden ingredients that help explain how specific recipes turn out correctly or not," said Greg Matera, PhD, professor of biology and genetics and co-senior author of the paper. "That's the first step in scientific discovery -- knowing that there are things we need to look for and then searching for them."

Beyond Yeast

Before now, a lot of this epigenetic research had been done in yeast -- single cell organisms that also use enzymes to lay chemical tags on histone proteins. This work has yielded many interesting findings and has led to the development of therapeutics. But some of this work has led to an oversimplification of human biology, leaving many questions about human health unanswered.

For instance, in complex organisms, enzymes in cells typically do more than one thing. One likely reason for this is that animals undergo cellular differentiation; human life begins as a single cell that differentiates into the various cell types needed for different organs, body parts, blood, the immune system, etc. This differentiation has to be maintained throughout life.

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Epigenetic breakthrough: A first of its kind tool to study the histone code

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