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University of Washington Team Developing ChIP System for High-throughput Epigenetic Analysis

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NEW YORK (GenomeWeb) — Researchers from the University of Washington have won $233,077 from the National Institute of General Medical Sciences to develop a novel chromatin immunoprecipitation platform, PIXUL-ChIP, that will integrate sample harvesting and chromatin shearing with immunoprecipitation on a single microplate for high-throughput epigenetic analysis.

The project, led by UW School of Medicine professor Karol Bomsztyk, is adapting an earlier microplate-based ChIP technology the group developed, called Matrix ChIP, which the group described initially in a paper in Nucleic Acids Research in 2008.

Bomsztyk, whose lab is focused on developing high-throughput epigenetic platforms to study epigenetic influence on inflammation associated with kidney disease, diabetes, multiple organ dysfunction in sepsis, and other disorders, told BAN that there is a significant unmet need for tools to explore epigenetic processes and exploit resulting discoveries in translational research and clinical applications.

Having used their Matrix ChIP method now for several years, the group has also realized how crucial automating sample preparation and processing will be for making the technology more broadly useful and feasible.

"Right now we do hundreds of chip assays per day, but sample prep is still slow. I work in the hospital and without better automation, I can tell you, we really have no chance, so we are working 24/7 because these kinds of technologies are desperately needed," Bomsztyk said.

The group's Matrix ChIP utilizes surface-immobilized antibodies on a 96-well plate and allows chromatin precipitation and DNA purification on one device.

According Bomsztyk and his colleages, Matrix ChIP allows for parallel profiling of an order of magnitude greater number of epigenetic modifications — chromatin and transcription events — than was previously possible with other ChIP methods. "Matrix ChIP is more sensitive than traditional approaches to detect DNA-protein interactions of less abundant proteins such as chromatin modifiers," the team wrote in the abstract for their newly funded project to further develop the technology.

Under this grant the researchers are looking to integrate sample harvesting and chromatin fragmentation — which on the current Matrix ChIP requires a separate, labor-intensive and inefficient test tube step. The group plans to call the resulting platform PIXUL-ChIP.

First, the researchers plan to build a what they call pixelated ultrasound (PIXUL) processor for high-throughput fast chromatin shearing. Then, they will attempt to combine sample harvesting and chromatin shearing with Matrix-ChIP's immunoprecipitation into an integrated microplate platform for epigenetic analysis.

The team also plans under the funding to test PIXUL-ChIP as a platform for studies of epigenetic changes at selected gene loci associated with human embryonic stem cell processes, the authors wrote.

"A highly efficient technology, PIXUL-ChIP will provide powerful means to simultaneously study multiple chromatin modifications and modifiers at gene loci in a wide range of systems, and as such will be a valuable platform for studying epigenetic processes, discovering epigenetic biomarkers, and testing novel drugs and their combinations," Bomsztyk and his colleagues wrote in the description of the project.

In a 2011 publication in BMC Molecular Biology Bomsztyk and his team also demonstrated that they could couple chromatin immunoprecipitation with measurement of other epigenetic processes, specifically with methylated DNA immunoprecipitation, or MeDIP, into a dual Matrix-ChIP-MeDIP platform.

Bomsztyk said the group is also potentially interested in combining automated and integrated sample processing with its Matrix ChIP-MeDIP technology.

But they are not naive about the immediate challenges ahead. "What we have learned from Matrix ChIP is that these [epigenetic] processes are very complex and how you prepare a sample is so important, since we want to capture what's in vivo and do it quickly so we don’t lose the information," Bomsztyk said. "It’s a real challenge we need to overcome to make sure we capture the right information."

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