The National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH), has awarded 10 grants, totalling $10.5 million, to develop revolutionary technologies that will help researchers identify millions of genomic elements that play a role in determining what genes are expressed and at what levels in different cells.
These multi-year grants are part of the Encyclopedia of DNA Elements (ENCODE) project, whose aim is to provide the scientific community with a comprehensive catalogue of functional genomic elements that will ultimately help explain the role that the genome plays in health and disease.
“The ENCODE project is providing a Rosetta Stone to understand how the sequence of the human genome forms the words that tell our bodies how to work at the molecular level,” said Eric D Green, MD, PhD, director of NHGRI, which directs and funds the ENCODE project. “By developing more revolutionary technologies for probing genome function, we expect to accelerate these efforts.”
Sequencing the human genome and identifying the small fraction of its bases that directly code for proteins were among the first steps in understanding how the genome functions. But the remaining larger fraction of functional genomic elements continues to be a mystery. In response, NHGRI launched the ENCODE project to identify all the functional elements in the human genome, along with the modENCODE project to identify the functional elements in the fly and worm genomes and a smaller effort examining the mouse genome. These projects have been rapidly releasing data to the research community.
These ENCODE efforts have collected large amounts of data with a wide variety of cell types, in many cases identifying key functional landmarks. By studying these landmarks, researchers can establish the locations of DNA sequences that perform a variety of essential functions.
“In an exciting development, researchers are beginning to use the ENCODE catalogues to understand how variation in the DNA sequence might influence diseases such as cancer and autoimmune disorders,” said Mike Pazin, PhD, a programme director for ENCODE in NHGRI's Division of Extramural Research.
Each person has one genome sequence that is basically the same in all cell types. In contrast, many genomic elements function in only some cell types. As a result, researchers must test many cell types using many different experimental approaches to develop a detailed inventory of the functional elements in the genome. Revolutionary technological improvements are required to discover and test the millions of functional elements and to learn more precisely what they do. Significant advances are also needed to establish whether information about these functional elements can be used in the diagnosis and treatment of disease.
“The current ENCODE efforts owe a good part of their success to technology development that has occurred over the last decade,” said Elise A Feingold, PhD, a programme director for ENCODE in NHGRI's Division of Extramural Research. “In addition to the technologies developed through this programme, ENCODE has benefitted enormously from advances fostered by NHGRI’s DNA sequencing technology initiative, the $1000 Genome Programme.”
The new technology development grants are focused on these areas:
Discovery of functional genomic elements will be addressed by funding projects for a new assay to identify RNA splicing elements, new assays to identify promoters and enhancers, as well as a project to improve assays for identifying functional elements by allowing these assays to work reliably using smaller samples. Splicing is the process that joins RNA copies of gene segments together to form mRNA, the blueprint for the production of proteins. Errors in splicing sometimes lead to human disease. Promoters specify the sites in the genome where genes begin and much gene regulation occurs. Enhancers are genomic elements that can turn on expression of nearby and distant genes. Mutations in promoters and enhancers can cause human disease.
Validation of biological elements will be addressed by funding projects for new methods with improved throughput, and a smaller project to improve accuracy by testing elements in their natural genomic context.
Computational analysis will be addressed by funding projects to predict regulatory protein binding and gene expression based on sequence alone, and to predict chromosomal interactions and link functional elements to their target genes.
Recipients of the technology development awards are:
Discovery of Functional Elements: Christopher Burge, Ph.D.; Massachusetts Institute of Technology, Cambridge, Mass.; $800,000 (over three years); Researchers will develop a new technology to catalog all of the RNA branch points that form in mRNA during splicing.
Mats Ljungman, Ph.D.; University of Michigan, Ann Arbor; $1,200,000 (over three years); Using bromouridine labeling of RNA, these researchers will develop new assays (BruChase-Seq and BrUV-Seq) to identity promoters and enhancers and to measure mRNA degradation and splicing kinetics.
Raymond David Hawkins, Ph.D.; University of Washington School of Medicine, Seattle; $460,000 (over two years); These researchers will improve the power of ChIP-seq assays to identify functional elements. ChIP-seq is one of the fundamental assays used in ENCODE to identify the locations in the genome that are attached to a particular protein.
Validating the Biological Role of Functional Elements
Barak Cohen, Ph.D.; Washington University in St. Louis; $1.1 million (over three years); These investigators will develop a method to test tens of thousands of promoters in primary cells.
Peggy Farnham, Ph.D.; University of California Davis; $540,000 (over two years); These investigators will test the function of genomic regions that bind large numbers of regulatory proteins. They will precisely remove parts of the genome, and ask how neighboring genes are affected.
Jason Lieb, Ph.D.; University of North Carolina at Chapel Hill; $1.3 million (over three years); Researchers will develop a method to test tens of thousands of regions of open chromatin for enhancer, promoter, insulator and silencer activity. In cells, the DNA of the genome is associated with proteins to form chromatin. Active regulatory elements in the genome are thought to reside in open chromatin, where the DNA is more exposed.
Tarjei Sigurd Mikkelsen, Ph.D.; The Broad Institute of MIT and Harvard, Cambridge, Mass.; $1.1 million (over three years); Researchers will test tens of thousands of elements in integrated reporters, for enhancer activity, insulator function and RNA processing regulation. Insulators are elements that form boundaries in the genome, dividing the genome into functionally separated neighborhoods.
Jay Shendure, M.D., Ph.D.; University of Washington, Seattle; $1.9 million(over three years); These investigators will develop methods to capture or synthesize tens of thousands of regulatory elements, and test them in cell lines and mice. Capture is a technique used to purify particular DNA sequences from a complex mix.
Computational Analysis: Christina Leslie, Ph.D.; Memorial Sloan-Kettering Cancer Center, New York City; $1.6 million (over three years); Investigators will develop new computational approaches to understand cell-specific gene expression programs, modeling cell-specific transcription as a function of chromatin state and transcription factor binding. Though the genome is essentially the same in all cell types, different genes are active in different cell types because different cell types have different regulatory proteins.
Guo-cheng Yuan, Ph.D.; Dana-Farber Cancer Institute, Boston; $530,000 (over two years); Researchers will develop novel computational methods to characterize chromatin states and predict chromatin interactions from these states. Functional elements that work together are thought to physically interact with each other by looping out parts of the genome that are in between.
NHGRI is one of the 27 institutes and centres at NIH. The NHGRI Division of Extramural Research supports grants for research and training and career development at sites nationwide.
NIH, the nation's medical research agency, includes 27 Institutes and Centres and is a component of the US Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.