Genetics beyond the genome: epigenetic structural insight

Beyond the DNA

Epigenetics is the field of science aimed at understanding how some genes are regulated without changes to the underlying DNA code occurring. Now, work that helps decipher some of the ways in which enzymes act on the proteins that surround DNA within cells reveals through X-ray diffraction how an acetylation complex fits like a halo over a histone substrate.

One class of the enzymes involved in this aspect of genetic chemistry and the proteins interactions are the histone acetyltransferases (HATs). Obviously enough, these enzymes act on DNA by modifying DNA-bound histone proteins and acetylating them. This process then dictates how histones interact with DNA and other proteins affecting processes such as DNA replication, transcription and repair.

Writing in the February issue of journal Structure, a team at The Wistar Institute in West Philadelphia, Pennsylvania, USA, describe the first high-resolution crystal structure of a yeast HAT, known as Rtt109, and one of its associated proteins. The structure and related work presented in the study provides important clues about how a particular acetylation of the amino acid lysine in the histone proceeds and so offers new insight into epigenetics and its relationship with health and disease.

Doubling up in a ring

Senior author Ronen Marmorstein, who heads Wistar's Gene Expression and Regulation Program, explains that two copies of Rtt109 bind to two copies of a chaperone protein to form a ring. This ring then fits on top of the histone like a halo. "We find that the type of chaperone dictates exactly how the enzyme affects the histone by determining the exact position of acetylation," explains Marmorstein. "The structure represents a nice model system for the regulation of protein acetylation, and teaches us something new about the biology of this enzyme, Rtt109."

Acetylation can act as a functional switch for proteins toggling them between one active form and another or between active and inactive forms. The researchers point out that Rtt109 can acetylate any of three specific lysines on histones; exactly which one is modified is determined by which chaperone escorts Rtt109 into place and so controls which type of activation is toggled. Histones are crucial DNA-associated proteins and so lysine acetylation has a profound effect on the histone's function, exposing a particular set of genes to be read, for instance.

Marmorstein and his colleagues, Yong Tang, Katrina Meeth and Hua Yuan, and collaborators at Johns Hopkins University School of Medicine, Université de Montréal, have demonstrated for the first time how Rtt109 associates with the chaperone Vps75. They have been working on the broader problem of acetylation for more than a decade and in that time its importance has been demonstrated again and again; researchers now have details of acetylation processes for over 2000 proteins including the histones. Marmorstein says that this is an entire web of communication taking place within cells that is directly attributable to protein acetylation, it is another level of complexity in a field that is already complex.

Pathway to acetlyation

"We have seen many different proteins over several different pathways become affected by acetylation, which can alter the processes of RNA metabolism, cell cycle control, cancer, and a number of different aspects of life. It looks like protein acetylation has much broader biological implications than initially appreciated," Marmorstein says.

"In many ways, it seems a lot like what we have seen in recent years with protein kinases and cell signalling," he adds. "What we are learning is that these HATs, and possibly other protein acetyltransferases, are regulated in much the same way. They have these profound effects within cells that we are only beginning to understand."

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.