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New tool for nucleosome charting
BOSTONóResearchers at Dana-Farber Cancer Institute recently developed a method for charting the positions of nucleosomes throughout the human genome. As nucleosomes are key gene-regulating molecules, this mapping tool could help uncover important clues for understanding various diseasesócancer being the focus of Dana-Farber but far from the only applicationóand their potential treatments. Also, the new tool may provide insights into the role of nucleosomes in potentially reprogramming an adult cell to revert to its original embryonic state, which could aid in discovery, development and diagnostic work that relies cloning.
The findings of Dr. David E. Fisher and his colleagues at Dana-Farber are a huge step forward because no earlier such work had been applicable to human biology. Similar analyses in simple organisms like yeast, Fisher notes, were not feasible for the much larger and more complex human genome, making the Dana-Farber method "the first global view of human nucleosome positioning." The technique provides clues for such critical information as where transcription factors bind, where transcription begins and ends, and the locations of other "biologically important structural features," he adds.
What this means for drug discovery is twofold, Fisher says. First, it potentially represents an entirely different way of conducting epigenetics of the human genome. In target identification and validation, he says, "Researchers can use this method to go beyond simply asking which genes are turned on or off, and also ask what is going on globally to the nucleosome positioning that reflects the state of a cell. For example, if cells are in process of dying from a particular drug, is there a pattern of nucleosome positions that is a signature of that cell's vulnerability to death?"
In short, researchers could be more precise in determining susceptibility of diseases to various candidate compounds, or could look at the patterns of nucleosome positions to get hints about what kind of compounds or activities are worthy of study for a particular disease.
"A second application that we've been thinking about is that there are specific drugs that focus on altering the epigenetic state of cells," Fisher says. "These types of drugs are undoubtedly impacting the positioning of nucleosomes in the genome, and until this point with this tool, we've been mechanistically blind to that aspect of things. Having that insight will improve discovery and development work in that drug area."
Nucleosomes are spherical packing units for DNA, which Dana-Farber describes as a length of DNA wrapped around a core, like ribbon around a spool. That spool is made up of proteins called histones, and the nucleosomes are located along the chromosomes like beads on a string.
Nucleosomes have multiple functions, including allowing several feet of DNA to be packed tightly into a cell's nucleus, Fisher says. They also regulate gene expression, or activity, by determining whether DNA sequences can be accessed by transcription factors, allowing the factors to regulate expression of a nearby gene. According to Dana-Farber, the researchers used gene microarrays, to which DNA associated with single nucleosomes was added. The nucleosomal DNA was derived from several cancer cell lines including melanoma and breast cancer, as well as several normal human cell types. A critical component of the analysis involved processing the data using computational algorithms devised by Dana-Farber faculty member Dr. X. Shirley Liu, and her postdoctoral fellow Dr. Jun S. Song. The researchers reportedly borrowed a computational technique from signal processing called "wavelet denoising" that revealed the patterns of positioned nucleosomes.