Scientists from University of North Carolina-Chapel Hill have created a new way to investigate epigenetic mechanisms important in diseases ranging from Alzheimer’s to cancers. This new research tool that is based on the fruit fly, is capable of cracking the histone code.
Histones are proteins that play critical roles in regulation of gene expression in animals and plants. This research tool can be used to better understand their function. This work led by Robert J. Duronio and A. Gregory Matera has been published in the journal Developmental Cell and opens avenues to explore the biology of a host of conditions and diseases. “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.”
One of the major modes of gene regulation is mediated by enzymes via chemical modifications on histone proteins. Histones can regulate access of enzymes to the DNA and a proper regulation results in normal conditions within the cell. The study (and occurrence) of such mechanisms which affect DNA indirectly are called epigenetic mechanisms. Epigenetic study is crucial because some cancer drugs in development target histones.
A lot of epigenetic research has been carried out on yeasts which, even though has unraveled significantly interesting mechanisms and led to important findings, fails to address the complexity of human biology. In yeasts (which are simple organisms), it is much easier to find the target and role of a histone modifying enzyme by introducing changes in the target histone so that it can no longer be modified. If the cells are still normal, there must be an alternate target for the enzyme. However, for mice and humans, the histone genes are scattered and numerous with a highly complex topography. Thus, replacing them with ‘designer’ histone genes becomes a monumental task.
“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.”
Matera, Duronio, and McKay led an effort to delete the histone genes in fruit flies and replace them with specific designer histone genes they created. As they demonstrate in the paper, they create designer genes by replacing the existing genes with a slightly altered version of the same histone gene. The designer gene is created such that the modifying enzyme cannot perform its role on this histone gene. In one of the histone-enzyme interactions the researchers got an expected result but in another such study they came across something unexpected. According to previous knowledge, disruption of the second histone-enzyme interaction should result in death. Interestingly, the flies lived and flew as normal flies do. This implied that this enzyme, supposedly vital for living must be involved in some other important process(es).
“There must be another target for that modifying enzyme,” Matera said. “There must be another hidden carrier of epigenetic information that we don’t know about.”McKay added, “This is a demonstration of the potential of our epigenetic platform. Going forward, we’re going to do a lot more experiments to identify more discrepancies and hopefully other targets of these enzymes. We’re on the ground floor of a long-term project.”
The original publication can be accessed here.