The goal of the ENCODE Project is to provide the biomedical community with a complete and biologically interpretable annotation of the human genome. This means discovering and mapping all parts of all genes, including exons, introns, promoters and cis-regulatory sequences, in previous phases of the ENCODE Project, the applicants of this proposal developed and applied robust, high-throughput, genome-wide methods for determining transcription factor occupancy, assessing DNA methylation, identifying RNA transcripts, and experimentally testing candidate regulatory elements and mutations. The combination of experiences from the previous phases with the resulting technology and analysis platforms and the existing, highly productive infrastructure of the applicants form the basis of this response to NHGRI's RFA-HG-11-024 (""""""""Expanding the Encyclopedia of DNA Elements (ENCODE) in the Human and Model Organisms""""""""). This application presents an ambitious proposal to expand the biological dimensions of ENCODE to include essentially all transcription factors for measurements of occupancy and to produce transcriptomes from hundreds of very specific cell types, and even single cells. The specific plan is to: 1) determine genome wide occupancy for all transcription factors and major cofactors with high resolution in two or more cell types;2) map and quantify all messenger RNA transcripts, microRNAs and other non-ribosomal RNAs in more than 300 well-defined, uncultured cell types;3) map DNA methylation state genome-wide at nucleotide resolution in more than 300 cell types;and 4) apply a high-throughput transient transfection assay system to test the impact of -2,000 candidate regulatory elements on gene regulation. All experimental work in this project will be evaluated by appropriate quality metrics, and after quality control, all data will be rapidly deposited in publi, freely accessible genome databases. In addition, computational analyses, including evaluation of comparative and population genomics data, will be integrated with the experimental production to help ensure quality and to capture information in forms useful to biologists, genomicists, and medical researchers. Completion of these Specific Aims will enable biomedical researchers to better and more rapidly understand the consequences of mutations in genomic disorders, including cancer, cardiovascular disease, and almost ail common diseases and, therefore, to more fully realize the potential of genomics to impact human health.
Interpreting the human genome sequence remains a daunting challenge. We cannot yet recognize genes and their regulatory elements based solely on primary DNA sequence. This ambitious ENCODE Project proposal leverages new advances in genomic technologies to radically improve the depth, breadth, and analysis of functional element annotations of the human genome, accelerating the impact on human health by tying the effects of mutations in functional elements to the misregulation of gene expression in disease.
|Jiang, Shan; Mortazavi, Ali (2018) Integrating ChIP-seq with other functional genomics data. Brief Funct Genomics 17:104-115|
|Grevet, Jeremy D; Lan, Xianjiang; Hamagami, Nicole et al. (2018) Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells. Science 361:285-290|
|Venkataraman, Anand; Yang, Kun; Irizarry, Jose et al. (2018) A toolbox of immunoprecipitation-grade monoclonal antibodies to human transcription factors. Nat Methods 15:330-338|
|Ramaker, Ryne C; Savic, Daniel; Hardigan, Andrew A et al. (2017) A genome-wide interactome of DNA-associated proteins in the human liver. Genome Res 27:1950-1960|
|Yang, Tao; Zhang, Feipeng; Yard?mc?, Galip Gürkan et al. (2017) HiCRep: assessing the reproducibility of Hi-C data using a stratum-adjusted correlation coefficient. Genome Res 27:1939-1949|
|Hsu, Sarah C; Gilgenast, Thomas G; Bartman, Caroline R et al. (2017) The BET Protein BRD2 Cooperates with CTCF to Enforce Transcriptional and Architectural Boundaries. Mol Cell 66:102-116.e7|
|Ramirez, Ricardo N; El-Ali, Nicole C; Mager, Mikayla Anne et al. (2017) Dynamic Gene Regulatory Networks of Human Myeloid Differentiation. Cell Syst 4:416-429.e3|
|Zhang, Yu; An, Lin; Yue, Feng et al. (2016) Jointly characterizing epigenetic dynamics across multiple human cell types. Nucleic Acids Res 44:6721-31|
|Hardison, Ross C (2016) Finding partners to play the music of regulation. Blood 127:1624-6|
|Hardison, Ross C (2016) A guide to translation of research results from model organisms to human. Genome Biol 17:161|
Showing the most recent 10 out of 40 publications