Kansas City, Mo. (July 11, 2008) - The Stowers Institute’s Shilatifard Lab has collaborated with the Institute’s Molecular Biology support facility to build a comprehensive library of histone mutants to study the fundamental mechanism of how genes are turned on and off. Development of the library allowed the team to identify previously unknown residues within histones that are required for proper histone methylation in yeast, a post-translational modification that is also catalyzed by the human childhood leukemia protein, MLL. The work was published in Nature Structural & Molecular Biology’s Advance Online Publication today.

     Each cell in the human body contains approximately 24,000 genes. Different cells express different sets of genes at different times. A key question in biology is how molecular changes signal genes to be turned on and off. Genes are contained on chromosomes, which in turn are made up of chromatin, a complex of DNA and proteins such as histones. Histones play important roles in gene regulation through an ongoing process of modification by methyl groups or small proteins such as ubiquitin. These molecules serve as markers that signal the cell to turn genes on or off.

     In earlier work using yeast as a model system, the Shilatifard Lab demonstrated that methylation of the H3K4 histone by a methyltransferase known as COMPASS requires monoubiquitination by the Rad6/Bre1 enzyme. Successful completion of these modifications requires sophisticated communication among the histones — a process called “crosstalk”. One of the human homologues of COMPASS is the MLL complex, which is involved in translocation-based childhood leukemia.

     Since Dr. Shilatifard and his colleagues identified this sophisticated crosstalk pathway in yeast, it has been demonstrated that this pathway is highly conserved from yeast to humans. Through their work with yeast cells, the Shilatifard Lab has made important contributions to understanding histone crosstalk, specifically as it applies to the human MLL complex.

     “We were excited to continue studying the function of histone crosstalk, but we needed some additional tools to do it well,” said Shima Nakanishi, Ph.D., Postdoctoral Research Associate and lead author on the publication. “Working with the Molecular Biology team, we were able to develop a comprehensive library of histone mutants that allows us to study histone crosstalk within nucleosomes in the regulation of chromatin modifications. With the help of the library, we have identified several new residues within nucleosomes regulating histone methylation by COMPASS — valuable information for our understandng of the role of MLL in the pathogenesis of childhood leukemia.”

     “One of the great advantages of conducting research at the Stowers Institute is that its support facilities do much more than just provide world-class, cutting-edge technical support,” said Ali Shilatifard, Ph.D., Investigator and senior author on the paper. “Support facilities, like Karen Staehling-Hampton’s Molecular Biology facility, actually collaborate with us to develop new techniques and tools that expand our research capabilites and move our work forward at a pace we could never achieve without their expertise. The outstanding support of support facilities sceintists, like Brian Sanderson in Molecular Biology, make impossible science possible for the Institute’s laboratories,” said Shilatifard.

     The Shilatifard Lab expects the library to expand their research opportunities and to serve as an important resource throughout the chromatin research community.

     “We have been contacted by many of our colleagues who would like to take advantage of this mutant library to address many fundamental questions regarding histones in the regulation of gene expression and development,” said Dr. Shilatifard.

     Learn more about Dr. Shilatifard’s work at www.stowers-institute.org/labs/ShilatifardLab.asp.

About the Stowers Institute
     Housed in a 600,000 square-foot state-of-the-art facility on a 10-acre campus in the heart of Kansas City, Missouri, the Stowers Institute for Medical Research conducts basic research on fundamental processes of cellular life. Through its commitment to collaborative research and the use of cutting-edge technology, the Institute seeks more effective means of preventing and curing disease. The Institute was founded by Jim and Virginia Stowers, two cancer survivors who have created combined endowments of $2 billion in support of basic research of the highest quality.