The human genome is regulated by hundreds of thousands of functional DNA elements that play pivotal roles in development and disease, yet remain poorly understood. Comprehensive identification and characterization of functional DNA elements is thus an essential goal with major implications for human health. Genomic DNA is organized into chromatin, a higher-order structure composed of DNA, RNA and proteins. Chromatin mapping technologies have emerged as a powerful means for identifying functional DNA elements, which are associated with characteristic chromatin structures. Mapping has enabled the systematic annotation of diverse types of functional elements, including promoters, enhancers and silencers, and new discoveries related to chromatin organization and genome regulation in health and disease. The proposed ENCODE data production center aims to vastly expand the catalog of functional elements in the human genome through production mapping of Protein, DNA and RNA constituents of chromatin. High-throughput pipelines will be used to map histone modifications, chromatin regulatory proteins and non-coding RNA binding interactions. These pipelines will be applied to designated ENCODE cell lines, embryonic stem (ES) cells and derivatives, induced pluripotent stem (iPS) cells and phenotypically diverse human tissues. Key histone modifications will also be mapped in representative cell and tissue types from multiple individuals, in order to address the extent and significance of inter-individual variation in chromatin landscapes and their relationships to genetic background. These multi-dimensional datasets will be integrated through innovative computational algorithms to identify sequences, motifs, variants and regulatory interactions that dictate chromatin state and functional element activity. Thus, the proposed project will dramatically increase the number, resolution and precision of functional DNA elements in the ENCODE catalog, and explicitly define causal sequences and physical interactions that mediate chromatin states and regulation in the human genome. All data will be rapidly released and made freely available to the scientific community.

Public Health Relevance

The human genome contains genes, which encode the protein machinery of cells, and thousands of regulatory elements that control when, where and how much protein is produced. These elements play pivotal roles in development and disease, yet remain poorly understood. The long-term goal of this project is to identify regulatory elements comprehensively and determine their functions in human health and disease.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HG006991-02
Application #
8548390
Study Section
Special Emphasis Panel (ZHG1-HGR-M (M1))
Program Officer
Feingold, Elise A
Project Start
2012-09-21
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$1,544,190
Indirect Cost
$484,316
Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Knoechel, Birgit; Roderick, Justine E; Williamson, Kaylyn E et al. (2014) An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet 46:364-70
Patel, Anoop P; Tirosh, Itay; Trombetta, John J et al. (2014) Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344:1396-401
Kheradpour, Pouya; Kellis, Manolis (2014) Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments. Nucleic Acids Res 42:2976-87
SuvĂ , Mario L; Rheinbay, Esther; Gillespie, Shawn M et al. (2014) Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 157:580-94
Mendenhall, Eric M; Williamson, Kaylyn E; Reyon, Deepak et al. (2013) Locus-specific editing of histone modifications at endogenous enhancers. Nat Biotechnol 31:1133-6