Jerry Workman, Ph.D., Investigator, and Bing Li, Ph.D., Senior Research Associate in the Workman Lab, have published evidence demonstrating that a combinatorial action of multiple protein domains is required to read a histone modification.
Published in today's issue of Science, their paper, "Combined action of PHD and Chromo domains directs the Rpd3S complex to deacetylate transcribed chromatin," used a novel approach that allowed the team to measure the protein complex binding to modified chromatin.
"When cells transcribe genes, that part of the chromosome is opened and susceptible to inappropriate use. Cells demarcate transcribed regions of chromosomes with a landmark — the lysine 36 methylation of histone H3," explains Dr. Li. "We found that combination of two critical protein domains within a histone deacetylase complex is essential for its recruitment to this modified chromatin in transcribed regions. This specific recognition re-closes the chromosome and ensures genome integrity during active transcription and maintains accurate transcription initiation."
Within chromatin-related complexes, compact structural parts of a protein, called "domains," are able to recognize specific histone modifications. However, until now it was unclear how such domains could target the correct protein complex to a specific site in the chromosome. In this case it takes the combined action of two protein domains to target the complexes to transcribe chromatin to re-close its structure.
The findings bear significantly on the understanding of Huntington's disease, which is marked by genetically programmed degeneration of neurons in certain areas of the brain.
"The histone modification we focused on in this study, K36 methylation, is catalyzed by the human protein HYPB that interacts with the Huntington's disease protein known as huntingtin," said Dr. Workman. "Our findings may one day assist in the design of therapeutic or preventive measures to intervene with the pathology of Huntington's disease and other polyglutamine expansion-related neurodegenerative disorders."
"One of the interesting aspects of this research is that it changes the prevalent 'one domain-one modification' paradigm in the field," said Robb Krumlauf, Ph.D., Scientific Director. "These findings may lead to future discoveries of many other combinations implicated in human diseases."
Additional contributing authors from the Stowers Institute include Madelaine Gogol, Programmer Analyst in Microarray; Mike Carey, Ph.D., Visiting Scientist from the David Geffen School of Medicine at UCLA; Daeyoup Lee, Ph.D., formerly a Postdoctoral Research Associate; and Chris Seidel, Ph.D., Managing Director of Microarray.
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.
Journal
Science