BOSTON—Researchersat Dana-Farber Cancer Institute recently developed a method for charting thepositions of nucleosomes throughout the human genome. As nucleosomes are keygene-regulating molecules, this mapping tool could help uncover important cluesfor understanding various diseases—cancer being the focus of Dana-Farber butfar from the only application—and their potential treatments. Also, the newtool may provide insights into the role of nucleosomes in potentially reprogrammingan adult cell to revert to its original embryonic state, which could aid indiscovery, development and diagnostic work that relies cloning.
The findings of Dr. David E. Fisher and his colleagues at Dana-Farberare a huge step forward because no earlier such work had been applicable tohuman biology. Similar analyses in simple organisms like yeast, Fisher notes, werenot feasible for the much larger and more complex human genome, making theDana-Farber method "the first global view of human nucleosome positioning." Thetechnique provides clues for such critical information as where transcriptionfactors bind, where transcription begins and ends, and the locations of other "biologicallyimportant structural features," he adds.
What this means for drug discovery is twofold, Fisher says.First, it potentially represents an entirely different way of conductingepigenetics of the human genome. In target identification and validation, hesays, "Researchers can use this method to go beyond simply asking which genesare turned on or off, and also ask what is going on globally to the nucleosome positioningthat reflects the state of a cell. For example, if cells are in process ofdying from a particular drug, is there a pattern of nucleosome positions thatis a signature of that cell's vulnerability to death?"
In short, researchers could be more precise in determiningsusceptibility of diseases to various candidate compounds, or could look at thepatterns of nucleosome positions to get hints about what kind of compounds oractivities are worthy of study for a particular disease.
"A second application that we've been thinking about is thatthere are specific drugs that focus on altering the epigenetic state of cells,"Fisher says. "These types of drugs are undoubtedly impacting the positioning ofnucleosomes in the genome, and until this point with this tool, we've beenmechanistically blind to that aspect of things. Having that insight willimprove discovery and development work in that drug area."
Nucleosomes are spherical packing units for DNA, whichDana-Farber describes as a length of DNA wrapped around a core, like ribbonaround a spool. That spool is made up of proteins called histones, and thenucleosomes are located along the chromosomes like beads on a string.
Nucleosomes have multiple functions, including allowingseveral feet of DNA to be packed tightly into a cell's nucleus, Fisher says.They also regulate gene expression, or activity, by determining whether DNAsequences can be accessed by transcription factors, allowing the factors toregulate expression of a nearby gene. According to Dana-Farber, the researchers used genemicroarrays, to which DNA associated with single nucleosomes was added. Thenucleosomal DNA was derived from several cancer cell lines including melanomaand breast cancer, as well as several normal human cell types. A criticalcomponent of the analysis involved processing the data using computationalalgorithms devised by Dana-Farber faculty member Dr. X. Shirley Liu, and herpostdoctoral fellow Dr. Jun S. Song. The researchers reportedly borrowed acomputational technique from signal processing called "waveletdenoising" that revealed the patterns of positioned nucleosomes.