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Germany's ImaGenes, Partners to Use $4M Gov't Grant in Array-Based Nutrigenomics Study

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By Justin Petrone

ImaGenes, a Berlin-based genomic research service provider, will take part in a four-year, €2.9 million ($4 million) project funded by the German Federal Ministry for Education and Research to study the epigenetic effects of nutrition on human health, the company said last week.

Researchers from the University of Kiel and the Research Institute for the Biology of Farm Animals in Dummelstorf are spearheading the project, called Vision Epifood, which will use arrays manufactured by Roche NimbleGen and Agilent Technologies together with custom-designed chips to study the influence of caloric restriction on gene expression, DNA methylation, and histone modification.

The goal of the project is to develop plant extracts that can be used in so-called "functional" food that could mimic restricted caloric intake in consumers, according to Frank Döring, head of the department of molecular intervention at the University of Kiel, who is leading the Epifood project.

"The aim of the project is to get a comprehensive view of gene expression and epigenetic modifications" resulting from alterations in diet, Döring told BioArray News this week. "In any organism, you will find a strong correlation between caloric intake and lifespan," he said. "What is the reason for this phenomenon? One hypothesis is that this impact is possible to study by looking at gene expression and modification of epigenetic markers."

More specifically, Döring said that previous research has shown that the presence of nicotinamide adenine dinucleotide-histone alternators in cells may be reduced when caloric intake is restricted. One study goal, therefore, is to examine the connection between caloric intake, NAD concentration, and activities that modify cell behavior.

"We will do caloric restriction in four different species — in Drosophila, pig, mouse, and humans — to identify, using microarrays, pathways of genes that are modified by caloric restriction," he said.

Phase One and Phase Two

Johannes Maurer, director of genomic products and marketing at ImaGenes, told BioArray News this week that the Epifood project will study the impact of alterations in diet on those four species using several different array platforms in a two-phase study.

In the first phase of the study, ImaGenes will screen five individuals from each species across six different tissues using chromatin immunoprecipitation (ChIP)-on-chip assays, Maurer said. To screen the human and mouse samples, ImaGenes will use 384,000-feature Roche NimbleGen promoter arrays. For Drosophila, the company will use a Roche NimbleGen 2.1-million feature whole-genome array. ImaGenes will have to design a custom array to investigate pig.

Steffen Hennig, ImaGenes' director of bioinformatics and services, told BioArray News this week that the company will use cap analysis gene expression to design the pig chip.

CAGE is a method developed by researchers at the Riken Institute and the firm DNAForm, both based in Yokohama, Japan. The method includes preparing and then sequencing on second-generation instruments concatamers of DNA tags derived from the initial 20 nucleotides from 5' ends of mRNAs, providing both expression levels and the transcriptional start sites at the same time.

Hennig said that ImaGenes has already partnered with DNAForm to use CAGE to identify promoter regions in pig. With that information obtained, ImaGenes is now left to design a tiling array that represents all promoter areas in the pig genome that can be used in the Epifood project.

After ImaGenes conducts its initial study and bioinformatics analysis, the company expects to narrow the coverage of its arrays to the significantly affected loci. ImaGenes will probably order the arrays using a 4x44,000-feature array or an 8x15,000-feature array manufactured by NimbleGen or Agilent.

Hennig said the study design was an example of how genomic services providers are integrating microarray and second-gen sequencing technologies. "We chose Agilent and NimbleGen's systems because, in the end, you can design whatever you like," Hennig said. "We combined this capability with sequencing, so you create de novo information and you are able to put that immediately onto a microarray system."

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After completing the first phase of the Epifood study, ImaGenes will use these custom multiplex arrays to screen 60 individuals from each species across six different tissues.

Maurer said that it's likely ImaGenes will use NimbleGen arrays in phase one because the firm, which in addition to Agilent also offers Affymetrix, has "very good experience" using NimbleGen's arrays in "routine ChIP-chip applications."

Maurer speculated that Agilent would be a "more convenient" platform for the custom arrays in the second phase of the study, since "they offer more variants in multiplex dimensions," but said that NimbleGen was also under consideration for the second phase as the company plans to debut more multiplex formats in the future.

According to Hennig, analyzing data across four different species on multiple different array platforms, some of them manufactured by different vendors, will be "difficult," but ImaGenes has already developed a prototype database to tackle the bioinformatics challenges of the study.

Results will be ordered on a genome-wide scale, and then using information in specific genes, the relationships between genes in one species and another will be determined by orthological relationships, Hennig said. "All genes and all species will be sorted by orthology," he said. "To extrapolate from one gene in pig to one in human can only be done by looking at neighboring genes and their functions."

Towards 'Epifood'

While the project with ImaGenes will provide information on the role expression and epigenetics appear to play in caloric restriction, the overall aim of the Epifood project is to identify a plant extract that can be used in foods that will mimic caloric restriction in consumers.

Döring said that, once identified, the extract will be screened in the Drosophila system for eventual adoption by food producers to create a new generation of functional foods. According to Döring, array technology could play a future role in food testing for response to such foods.

"I think there is a market for this," he said. "You can use gene-expression profiles in a diagnostic to determine your relationship to nutrition."

Maurer concurred that nutritional diagnostics could be a "stable niche" for arrays, which are being replaced in some markets by second-gen sequencing.

"Sequencing is getting cheaper and cheaper, and I think a lot of array applications will shift to sequencing," Maurer said. "A stable niche [for arrays] will be all kinds of diagnostics.

"It is much too complicated to handle data that comes from sequencers [in diagnostics] and this won't change in the next five years or so," he added. "I think the future applications of arrays will be in the diagnostics area, for example, in susceptibility to certain nutritional regimens."

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