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.
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.
|Gupta, Rajat M; Hadaya, Joseph; Trehan, Aditi et al. (2017) A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression. Cell 170:522-533.e15|
|Liau, Brian B; Sievers, Cem; Donohue, Laura K et al. (2017) Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance. Cell Stem Cell 20:233-246.e7|
|Wang, Xiaofeng; Lee, Ryan S; Alver, Burak H et al. (2017) SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nat Genet 49:289-295|
|Shema, Efrat; Jones, Daniel; Shoresh, Noam et al. (2016) Single-molecule decoding of combinatorially modified nucleosomes. Science 352:717-21|
|G Hendrickson, David; Kelley, David R; Tenen, Danielle et al. (2016) Widespread RNA binding by chromatin-associated proteins. Genome Biol 17:28|
|Drier, Yotam; Cotton, Matthew J; Williamson, Kaylyn E et al. (2016) An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma. Nat Genet 48:265-72|
|Xie, Qi; Wu, Qiulian; Kim, Leo et al. (2016) RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation. J Clin Invest 126:2757-72|
|Flavahan, William A; Drier, Yotam; Liau, Brian B et al. (2016) Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529:110-4|
|van Galen, Peter; Viny, Aaron D; Ram, Oren et al. (2016) A Multiplexed System for Quantitative Comparisons of Chromatin Landscapes. Mol Cell 61:170-80|
|Rotem, Assaf; Ram, Oren; Shoresh, Noam et al. (2015) Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state. Nat Biotechnol 33:1165-72|
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