ENCODE Prepares For The Next Genome Data Explosion

A Challenging And Worthwhile Objective
Last week ENCODE hosted a three-day Research Applications and Users Meeting for the broader research community. The Encyclopedia of DNA Elements (ENCODE) Consortium is a global collaboration of research groups funded by the National Human Genome Research Institute (NHGRI). Members of the ENCODE Consortium are addressing the challenge of creating a catalog of the functional elements of the human genome that will provide a foundation for studying the genomic basis of human biology and disease.

For Phase 3, the ENCODE Consortium project is using next-generation technologies and methods to expand the size and scope of catalog content created in earlier phases. ENCODE’s Phase 3 analysis will require approximately millions computing core hours and will generate nearly one petabyte of raw data over the next 18 months. It is hardly surprising then, that in addition to keynote lectures and presentations by distinguished speakers, the ENCODE 2015 meeting agenda was packed with hands-on workshops and tutorials designed to provide attendees the knowledge and skills they will need to access, navigate, and analyze ENCODE data. As announced last week, the ENCODE Consortium’s Data Coordination Center (DCC), located at Stanford University, has adopted the DNAnexus platform, enabling virtually unlimited access to data and bioinformatics tools in support of Phase 3 research.

Seamless Live Demo
Many large-scale genomics studies have been limited by the lack of required computational power and collaborative data management infrastructure. The power of the DNAnexus platform was demonstrated firsthand when roughly 150 ENCODE workshop attendees, using the DNAnexus platform, launched the RNA-Seq processing pipeline in unison on a sample dataset. While the ensuing demand for data retrieval and processing would bog down a typical institutional computing resource for hours or days, possibly “freezing out” any additional user requests during that time, the cloud-based DNAnexus platform simply scaled, as usual, to meet demand. Every workshop participant’s workflow was processed at full speed.

encode user meeting

More Than Scale
Although a scalable solution capable of processing thousands of datasets was a key requirement for the DCC, it was not the only factor in its decision. The development of version-controlled ENCODE pipelines is a priority in the current phase of the ENCODE project to ensure that data released to the public are consistently processed. Tasked with centralizing the project’s raw sequencing data with uniform metadata standards and bioinformatics analysis, the DCC will also take advantage of the DNAnexus platform to supply the Consortium with a secure and unified platform already connecting thousands of scientists around the world, and to provide transparency, reproducibility, and data provenance for consistency amongst ENCODE pipelines and results. Stanford has open-sourced the ENCODE pipelines on GitHub, and they are also available in a public project on the DNAnexus platform, along with other public data and pipelines.

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DNAnexus is proud to support Stanford University, the ENCODE DCC, which serves as a data warehouse and processing hub for the ENCODE project. We believe cloud-based solutions for genome projects will have a blockbuster impact on accelerating genomic medicine.

New ENCODE Paper Reveals Remarkable Chromatin Diversity at Regulatory Elements

Today marks a major milestone for the ENCODE consortium! More than 30 papers will be published today in Nature, Genome Biology, and Genome Research from teams of scientists working on various facets of the project.

One of those, a publication in Genome Research, reports on a surprising level of heterogeneity among patterns of chromatin modifications as well as nucleosome positioning around regulatory elements such as transcription factor binding sites in the human genome. In the past, these genomic elements have been studied primarily by averaging patterns of chromatin marks across populations of sites, leading to the perception that patterns were much more uniform. The nucleosome positioning sequence data mapping and analysis was performed on the DNAnexus platform.

Lead author Anshul Kundaje was a postdoc for Serafim Batzoglou and Arend Sidow at Stanford University during the project reported in the paper. Now a research scientist at MIT, Kundaje says the work was an integral part of the ENCODE consortium’s efforts to elucidate functional elements in the human genome. The scientists looked at 119 human transcription factors and regulatory proteins to better understand how nucleosomes are positioned and how histone modifications are made around binding sites. In the paper, the authors report that asymmetry of nucleosome positioning and histone modifications is the rule, rather than the exception.

Kundaje and his colleagues relied on ChIP-seq data for the 119 transcription factors in a variety of cell types, with corresponding data for histone modifications. They also generated similar data for nucleosome positioning. To improve accuracy, the team sequenced extremely deeply, ultimately generating some 5 billion reads on the SOLiD sequencing platform. “The data sets were incredibly massive,” Kundaje says. “Processing these data sets locally was quite a challenge.” The group turned to DNAnexus, uploading their sequence files to the cloud and preprocessing the data with the company’s probabilistic mapping tool. “DNAnexus made that process incredibly simple,” he adds.

Figure 1:The mapping of the 5 billion reads was performed using the DNAnexus mapper.

Using a new tool they developed — the Clustered AGgregation Tool (CAGT) for pattern discovery — the scientists found that nucleosome positioning and histone modification at transcription factor binding sites is far more diverse than was previously thought. Rather than averaging across the regions as most studies have done, the new clustering tool was able to analyze the differences in magnitude, shapes, and orientation of the many patterns identified.

“What we found is that the results you get from the clustering approach are dramatically different from what you get by simply averaging across all types,” Kundaje says. “We found a large diversity of patterns of histone modifications as well as nucleosome positioning around almost every transcription factor binding site.”

Even the well-known and remarkably well studied transcription factor CTCF, long established as an insulator, was found to have surrounding chromatin patterns pointing to other functions throughout the genome.

Figure 2: Analysis using CAGT reveals the surprising diversity of patterns of an active chromatin mark H3K27ac around the binding sites of the CTCF protein that is well-known for its repressive insulator role.

The authors used their clustering tool to group the patterns into some 25 distinct signatures “that completely capture the diversity of all the modifications across all binding sites in a variety of cell types,” Kundaje says. The method uses ‘metapatterns’ to explain that diversity, and that information can reveal the function of these elements in context. “By accounting for combinatorial relationships between various binding events and how they affect chromatin, this gives you a more complete biological sense of what a transcription factor is doing in a cell type,” he adds.

Kundaje is already following up on this study by looking at other species to see whether the heterogeneity of modification patterns holds true in other organisms. He continues to use DNAnexus for analysis of sequencing data, especially in read mapping, quality control, and genome browsing, he says.

Using DNAnexus for the team’s ENCODE study “made the process significantly easier,” Kundaje adds, noting that the cloud provider’s direct integration of the genome browser was particularly helpful. DNAnexus allowed Kundaje and his colleagues to go from data to visualization with minimal processing steps in between, he says. “It frees up your time to focus on the more interesting work.”

For a glimpse of some of Kundaje’s data, DNAnexus has made the 20 samples available on DNAnexus in the Public Data folder, called Encode. Click here to sign up for a free account.

Check out the Kundaje et al. paper “Ubiquitous heterogeneity and asymmetry of the chromatin environment at regulatory elements.”