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Roadmap Epigenomics Consortium Members Publish Study Collection

NEW YORK (GenomeWeb) – Several studies in the Nature family journals are offering a look at results from the National Institutes of Health's Roadmap Epigenomics Consortium, an NIH Common Fund-supported effort to untangle regulatory features in human cells.

The project "set out to generate a reference map of the human epigenome by systematically profiling these marks in more than 100 different primary tissues and cell types," co-leader Manolis Kellis, a computer science researcher affiliated with the Massachusetts Institute of Technology and Broad Institute, told reporters during a telephone press briefing yesterday.

In a study online today in Nature, Kellis and co-authors provided an integrative analysis of 111 reference epigenomes produced from primary tissues and cell types, along with embryonic stem cells undergoing differentiation.

The suite of regulatory features in these cells — including histone marks, DNA methylation and accessibility profiles, and gene expression patterns — was discerned with the help of sequencing done in combination with chromatin immunoprecipitation, DNaseI digestion, bisulfite, methylated DNA immunoprecipitation, and other assays.

The analysis also included information for 16 cell types tested by the ENCODE project, a National Human Genome Research Institute-funded effort to characterize the regulatory features in a smaller core set of cell types.

As such, the results expand on those provided by the ENCODE project, taking a broader look at tissues throughout the human body, co-author and ENCODE researcher John Stamatoyannopoulos, a genome sciences researcher from the University of Washington, told reporters yesterday.

By assessing their newly generated epigenomes alongside genome-wide association study data, meanwhile, researchers noted instances of overlap between loci implicated in 58 GWAS and sites in the genome that appear to participate in tissue-specific gene regulation.

For instance, variants associated with type 1 diabetes, rheumatoid arthritis, and/or multiple sclerosis tended to turn up at sites with regulatory activity in immune cells. Likewise, the team uncovered an over-representation of height-linked loci in regulatory regions active in stem cells and blood pressure-linked loci overlapping with regulatory regions active in heart tissue and so on.

But there were surprises, too, including overlap between variants from Alzheimer's disease GWAS and regulatory sites with tissue-specific activity in immune cells, hinting at ties between the genetic predisposition for Alzheimer's and immune activity.

To look at this more closely, members of the team developed and did experiments on a mouse model of Alzheimer's disease with epigenetic and gene regulatory features in its hippocampus that closely resemble those described in humans with the condition.

There, they saw a decline in neuronal activity that appeared to reflect epigenetic changes in neuronal tissue, Kellis said, but a jump in immune-related processes that may be mediated by monocyte-like glial cells in the brain.

Data from the Roadmap Epigenomics Consortium have been released to the research community as they were generated to serve as a resource for those aiming to understand regulatory features in the context of human development and other traits and diseases.

Appearing alongside the integrative analyses were several companion papers that "show how the map of the epigenomes help us uncover gene regulatory mechanisms in both normal and pathological conditions," explained co-author Bing Ren, a researcher affiliated with the Ludwig Institute for Cancer Research and the University of California at San Diego.

For instance, some members of the team delved deeper into the epigenetic processes behind stem cell differentiation — including transcription factor binding shifts or changes in chromosome folding and architecture. Others considered interactions between maternally and paternally inherited versions of the same chromosome.

Yet another analysis pointed to an overlap between cancer-related genetic alterations and epigenetic profiles found in the cancer's originating tissue, suggesting such features could prove useful for tracing metastatic tumors back to a primary site.

Papers appearing in Nature Protocols, Nature Methods, Nature Biotechnology, Nature Neuroscience, Nature Immunology, and Nature Communications delved into technical and analytical aspects of the project as well as other applications for the datasets.

Among these is a paper by investigators at Washington University and the University of California at San Francisco that presented information on a WashU Epigenome Browser tool designed to visualize and interpret regulatory data from both ENCODE and the Roadmap Epigenomics Consortium.

While data generation has wrapped up for the Roadmap Epigenomics Consortium, group members are part of an ongoing international effort known as the International Human Epigenome Consortium, which will continue exploring new cell types, epigenetic marks, and more.