The expanding field of epigenetics focuses on the multiple influences on DNA and surrounding molecules that determine whether genes are turned on or off during development and disease processes.

A consortium of scientists, led by Albert Jeltsch at Jacobs University, Breman, Germany, Yoichi Shinkai at Kyoto University, Japan, and Xiaodong Cheng at Emory University, has now discovered new non-histone targets for one enzyme previously believed to modify only histones--the group of proteins that creates tightly bundled packages of DNA strands. The research is reported online in the journal Nature Chemical Biology.

These modification enzymes, called protein methyltransferases, add methyl groups to lysine amino acids within the histones and change their influence on gene expression. The newly identified non-histone targets add yet another influence on gene expression in addition to the already-known DNA methylation and histone modifications in the epigenome.

The international research team has found that a histone methyltransferase called G9a adds methyl groups to other proteins in addition to histones and changes the behavior of those proteins. The researchers used a peptide array technology called SPOT to identify the new enzyme targets.

"This discovery broadens our view of methyltransferases and tells us that epigenetic regulation in cells is even more complicated than we thought," says principal investigator Xiaodong Cheng, PhD, professor of biochemistry at Emory University School of Medicine and a Georgia Research Alliance Eminent Scholar.

"We have known for some time that we had a great deal more to discover about methyltransferases. This is an important piece of the puzzle, and additional research will continue to help us unwind the multiple mechanisms involved in epigenetic gene regulation."

emory

"This result is important for the entire field of gene therapy," notes High, a past president of the American Society of Gene Therapy. "Gene transfer has been in clinical trials for over 15 years now, and although it has an excellent safety record, examples of therapeutic effect are still relatively few. The results in this study provide objective evidence of improvement in the ability to perceive light, and thus lay the groundwork for future studies in this and other retinal disorders," said High.

The pace of moving from pre-clinical discoveries into clinical trials has typically been slow in the field of gene therapy due to the breadth of expertise required, ranging from in-depth knowledge of the disorder to detailed understanding of vector design, manufacture, and pre-clinical evaluation. The complexities of regulatory oversight at both the federal and local levels also present challenges. Through the Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia has developed concentrated expertise and substantial resources to facilitate the "bench to bedside" translation of gene therapy.

The scientists at the Clinical Vector Core at CCMT have over 30 years experience in the biopharmaceutical industry and in 2007 were awarded a National Institutes of Health contract for clinical grade vector production for trials throughout the United States, attesting to the quality of their vector manufacture. The CCMT's dedicated regulatory affairs support has specialized expertise in clinical gene therapy and coordinates trial approvals from multiple scientific and ethic review committees, manages the study activities at all clinical sites, and ensures compliance with international quality standards for conducting, monitoring, and reporting clinical trials.

The clinical trial was sponsored and primarily funded by the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia. Research support was received from The Department of Ophthalmology at the University of Pennsylvania, the F.M. Kirby Foundation, the Foundation Fighting Blindness, Research to Prevent Blindness, the Macula Vision Foundation, the Paul and Evanina Mackall Foundation Trust at the Scheie Eye Institute, the Rosanne H. Silbermann Foundation, the Italian Telethon Foundation, the Associazione Italiana Amaurosi Congenita di Leber, the National Center for Research Resources, the Howard Hughes Medical Institute, the National Eye Institute of the National Institutes of Health, private philanthropy, and an anonymous donor who is committed to advancing pediatric medicine through maximizing the potential of gene therapy.

chop/ and uphs.upenn/