A European consortium aims to generate more than 100 reference epigenomes of hematopoietic cells in an effort to accelerate clinical research, biomarker discovery, technology, and drug development for epigenetic targets.
The consortium, called the Blueprint of Haematopoietic Epigenomes project, or Blueprint for short, has secured €30 million ($40.6 million) from the European Union's Seventh Framework Program and includes 41 institutes, universities, and companies.
The project, which is expected to last up to five years, kicked off last month with a joint meeting with the International Human Epigenome Consortium at the Royal Netherlands Academy of Arts and Sciences, where participants discussed the project's central goals.
Hendrik Stunnenberg, Blueprint's coordinator, told Clinical Sequencing News this week that the successes of a number of smaller EU epigenomic projects suggested "a clear incentive to continuing and adding an epigenomic dimension to the genome research going on."
Stunnenberg said that the initiative, which plans to integrate its data with that of other groups, including the IHEC, the Encyclopedia of DNA Elements project, and the 1000 Genomes Project, has long-term and short-term goals.
In the short term, the project's main thrust will be to generate an epigenome resource that will give "clinicians, biologists, [and] people working in the field … access to the data as soon as possible," said Stunnenberg.
Long-term goals include exploring epigenetic variation; developing new technologies for sequencing and analysis, and working to identify epigenetic drug targets and associated therapies.
Stunnenberg said that the project will use a variety of sequencing techniques that will be spread over three main centers according to their expertise: DNA methylation bisulfite sequencing will take place at the National Genome Analysis Center in Barcelona, Spain; Stunnenberg's department at Radboud University in the Netherlands plans to do ChIP sequencing; and the Max Planck Institute for Molecular Genetics in Berlin will perform RNA sequencing.
"DNA methylation will be done with bisulfite sequencing at high resolution," he said. "The transcriptome will be done completely and very deep so we have a good overview … and then we will also be looking at a larger number of epigenetic marks that are very instructive to telling what functions you can attribute to regions."
Blueprint is divided into four "research areas" that address different aspects of the broader project.
In the first research area, the group plans to create a roadmap of differentiation — from the hematopoietic stem cell through various multipotent precursor cells to mature cells — by defining the reference epigenomes of about 50 or more primary healthy blood cells at different points of differentiation and comparing them to a similar number of counterparts from cancer patients.
"This will give a framework to place cancers, and to say where [different cancers] fit into the differentiation pathway," Stunnenberg said.
He said the reference will help clarify disease-linked methylation in the context of natural variation. "Now we [can] say, 'Ah ha, there is DNA methylation that correlates with some disease A, but we don't know what the variation at that position is in the natural population,' so that's one good reason to determine an epigenome to get an idea of the variation at the various positions. Is it invariable? Highly dynamic? How dynamic, we don’t know."
Under the project's second research area, the partners plan to "address the causes and consequences of epigenetic variation and utilize this knowledge for improved diagnostics of human diseases," according to the project website.
Stunnenberg said biomarker analysis will be a key part of this project component. "We'll obviously have some cancers in there, so when we have the complete setting of the normal differentiation pathway and different transformation processes, we can very likely filter out those regions that are important for self renewal and transformation [in hematopoietic cells]," he said.
"Since we have a complete picture, [we] can remove everything that is differentially linked, that is part of a normal program, and find the [areas] where [cells] are deviating [in disease]."
He said the group plans to start with deep analysis of a small number of initial cancer samples in the reference group and then look at a small number of loci in large numbers of samples.
Also as part of this second research area, the group plans to conduct what it believes will be the first comprehensive epigenome-wide association study of a human disease — type 1 diabetes. The initiative said it chose T1D for this project because consortium partners have already conducted a successful pilot study demonstrating epigenetic involvement in the disease.
The additional research areas are drug discovery and technology development: two projects where some of the consortium's commercial companies will play a role. Commercial partners include Oxford Nanopore Technologies, Novartis, Halo Genomics, Cellzome, Genomatix, Epigenomics, and other tool providers and drug makers.
Stunnenberg said that one goal of the corporate partners will be developing technologies to reduce the sample sizes required for the epigenetic sequencing planned in other areas of the consortium.
"One of the major bottlenecks in epigenome analysis at the moment," Stunnenberg said, "is the amount of material you need. So efforts are going on, not only in Blueprint, but in other projects, to get to miniaturization, to microfluidic systems, so you need less material, and can do smaller biopsies to do that analysis."
"That is a trend that has already started, but [there are not] yet standardized protocols and machines and procedures to do that on small cell numbers," he said.
Stunnenberg declined to go into detail about the contributions of all of the group's commercial members, but Halo Genomics announced earlier this month that under the project, it plans to develop its HaloPlex PCR technology to capture genomic regions for targeted methylation analysis in a large number of samples.
In addition, the project website notes that partner Diagenode "will develop a liquid handling robotics unit for automatized chromatin-IP on small volumes," while another partner, Sigolis, "will apply its proprietary technology to develop a ChIP tailored microfluidic device."
The website also notes that Oxford Nanopore will be working to overcome read and cost-intensity limitations of whole-genome bisulfite sequencing.
"The minute [these companies] have technology they think we could use, we would be a tester site, or work to co-develop," Stunnenberg said. Likewise, "they, of course, have an interest in hearing from the field what directions it is taking, so that close collaboration and exchange is certainly mutually beneficial."
A large number of the project's samples are coming from the Cambridge BioResource and the Wellcome Trust Case-Control Cohort, Stunnenberg said.
The Wellcome Trust Sanger Institute will perform whole-genome sequencing on the same individuals, though this sequencing will not be a part of the Blueprint project itself, he said. Blueprint will also have access to cancer genome data generated by the International Cancer Genome Consortium.
As the project progresses, a "large team" of bioinformaticians, headed by the European Bioinformatics Institute, will analyze the data. EBI will host a large part of the raw data in its archives and make it available to the research community.
Stunnenberg said that the consortium model is necessary for the scale of the project.
"Sure, a department like my own could probably do all the sequencing involved in three or four years with the machines we have, but we would not be able to get all the material and do all the quality control and analysis, drug screening, and biomarkers," he said. "The research has become too big."
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