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European PEP-NET Consortium Aims to Integrate Epigenetic Data With Mathematical Models

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NEW YORK (GenomeWeb) – A new consortium has received €4 million ($4.6 million) in European Union Horizon 2020 funding to develop new tools and models for translating epigenetic data into therapeutically actionable outcomes.

The effort, called Predictive Epigenetics, or PEP-NET, will commence next month and involves scientists from 11 institutions and companies, as well as five partner organizations. Participants aim to develop predictive modeling frameworks to better understand epigenetic mechanisms, while encouraging the development of new technologies and therapies.

As part of PEP-NET, the investigators will also fill 15 PhD positions, with the hope of grooming a new cadre of epigenetics experts in Europe that are equally as comfortable with theoretical as well as experimental approaches. The consortium is funded for the next two years.

Ultimately, consortium members hope that PEP-NET will result in patient-specific models that will be used to develop predictions for disease diagnosis, prognosis, and drug response based on epigenetic variation. They also believe their projects could eventually enable in silico trials for epigenetic drugs by providing validated models for a range of epigenetic mechanisms.

Leonie Ringrose, a professor of quantitative biology at Humboldt University of Berlin, is coordinating the consortium. She said that she and others initiated PEP-NET to fulfill a long-term goal of combining quantitative experiments and mathematical modeling to understand epigenetic regulation in vivo, and to, in her words, bring the "crisp formalism" of mathematical modeling to resolve the questions of epigenetics.

According to Ringrose, the field needs such models to analyze the large amounts of data being produced by new technologies. While in the past, much of the focus was on generating epigenetics data, the availability of next-generation sequencing applications, such as MethylSeq or genome-wide methylation arrays has left investigators trying to make sense of it, let alone turn it into actionable clinical information.

"The omics revolution has swamped epigenetics," said Ringrose. "But data alone doesn't do it unless you have some kind of unifying theoretical idea of where all of those data fit together. The field went through a phase that hasn't finished where people generate huge amounts of data," she said. "In my mind, some of the deeper questions were getting lost."

In addition to Humboldt University, other PEP-NET consortium members include the Max Planck Institute for Molecular Genetics in Munich; the John Innes Center in Norwich, UK; the University of Copenhagen; the Institute for Biomedical Research in Basel, Switzerland; the European Research Center for Biology and Medicine in Strasbourg, France; the Max Delbruck Center for Molecular Medicine in Berlin; the University of Oxford; the University of Naples; Saint Raphael Hospital in Milan; and the Belgian epigenetics company Diagenode.

Five other organizations and companies are considered to be partners of PEP-NET. These include Oxford, UK-based Oxford Biodynamics; Oxford Nanoimaging, another Oxford firm that manufactures super-resolution microscopes; the University of Adelaide in Australia; the University of Pennsylvania; and the University of East Anglia in the UK.

The core concept of PEP-NET is not to produce a specific scientific result, but rather to overcome some of the challenges in uniting biology and mathematics, Ringrose said. Part of that will include the hiring of the new researchers to "combine quantitative experiments with predictive theoretical models, and to apply this knowledge to basic and applied questions of epigenetic function."

PEP-NET also includes three work packages that aim to investigate single-locus regulation, genome-wide targeting, and 3D genome organization. For the single-locus regulation work package, researchers will engage in projects to observe epigenetic regulation at the single-locus level in real time, with an eye on how epigenetic regulators sense gene expression states, how these states are maintained by an epigenetic memory, and how the states can be altered.

"The idea is how does a single gene even work?" said Ringrose. "How does it get regulated? How does it have epigenetic memory? Can we model that?"

Being able to quantitate the relationship between DNA sequence and regulatory output could also be used to generate patient-specific predictive models, Ringrose noted. As part of the work package, the PEP-NET researchers will develop models in which specific parameters represent molecular components. Predictions will then be tested through experiments and comparison of reporters at certain genomic loci.

PEP-NET's second work package is devoted to genome-wide targeting. Researchers will attempt to determine how epigenetic regulators find their target sites. They are also interested in learning how targeting survives dynamic chromatin changes during cell cycle and DNA damage. Since the misexpression of a regulatory protein can cause disruption leading to numerous cancers, understanding the rules for targeting is necessary to understand normal function, disease, and therapeutic interventions based on inhibitors of epigenetic enzymes, Ringrose maintained.

PEP-NET's third work package is focused on 3D genome organization. In this package, researchers will seek to answer how long-range chromatin interactions change during development, metabolic cycling, and disease. They are also interested in the outcomes of those interactions, as well as their underlying mechanisms. Oxford Biodynamics will play a role in this work package by using its EpiSwitch technology to to look at high-order chromatic contacts, Ringrose noted.

OBD's EpiSwitch platform centers on a class of epigenetic biomarkers known as chromosome conformation signatures (CCS) that the company claims can be used to analyze changes in genomic regulation before the results of epigenetic changes manifest themselves. The company employs arrays, sequencing, and real-time PCR to characterize these markers. OBD markets the tool to pharmaceutical firms for use in reducing time to market, failure rates, and drug discovery costs.

By participating in PEP-NET, the firm said in a statement that it is "well positioned to access commercial opportunities" arising from new applications of its technology, while it supports an improved understanding of epigenetic controls and mechanisms.

CSO Alexandre Akoulitchev agreed with Ringrose that data generation in recent years has surpassed scientists' ability to analyze it. "Rather than finding the needle in the haystack," he said, "we are just making the haystack bigger." He characterized PEP-NET as an effort to "recognize that biology and epigenetics is becoming a more precise science and to bring in mathematicians with modeling to join the dots between carefully chosen experimental models and mathematical models."

"That way we will start operating in a rigorous way of precise sciences, like physics or biophysics, in order to build up measurable outcomes that can be judged on their delivery," he said.

OBD has a "high-level interest" in understanding possible therapeutic applications, while looking at expansion of biomarker applications, Akoulitchev added. "For us, [PEP-NET] opens fascinating opportunities to identify very interesting biomarker targets across the non-coding part of the genome," he said. He noted that the use of mathematical modeling within the project should also provide information on connections between metabolic cycles, and coding and noncoding transcriptional events.

"We are well aware how much the industry is looking for robust biomarkers with predictive and prognostic disseminating power," said Akoulitchev. "This is very much a question of understanding epigenetic controls," he said.

While the outcomes of PEP-NET may very well trickle down to drug development programs in the future, Ringrose noted that it is the training of 15 new researchers within PEP-NET that could impact the epigenetics field for years to come.

"We are starting a completely new way of thinking," said Ringrose. "The core of it is to combine theory and experiments to tackle fundamental questions of epigenetics and things that can be applied to diseases and commercial applications," she said. "We want to get these new people to hop between theory and experiment. This would hopefully see the creation of a new culture where those two sides are no longer excluded from each other."

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