The overall aim of this proposal is to establish a comprehensive, high-quality, high-resolution catalogues of human and mouse DNasel hypersensitive sites (DHSs) spanning all major tissue lineages. Building on the prior success of the UW ENCODE center, we plan to localize DNasel hypersensitive sites, to define the locations of DNasel footprints therein, and to continue to provide relevant synergistic annotations including RNA-seq, histone modifications, and CTCF, as well as DNA methylation. The overriding focus of our production effort has been on data quality. Accordingly, samples will be rigorously screened in a pipeline fashion, with only a select set advancing to whole-genome data collection. To ensure the broadest possible coverage of both unique and non-unique genomic territories, we will employ a higher resolution, higher coverage sequencing strategy than the prior project period, significantly enhancing the information content of the data. This proposal integrates the UW-FHCRC Mouse ENCODE Center, which will be closely aligned with the human project to generate a comparative catalogue of regulatory DNA in carefully matched cells and tissues, providing an unparalleled resource. Since DNasel hypersensitive sites are generic markers of a broad spectrum of human cis-regulatory sequences, the utility of the catalogue will be greatly enhanced by the classification of DHSs into major functional categories including promoters, distal elements (enhancers, LCRs), and insulators. We plan to systematically connect distal DHSs with their cognate promoters and to perform in vivo validation of these connections using nuclease-mediated knockouts of distal DHSs in somatic cells.

Public Health Relevance

DNasel hypersensitive sites mark the locations of regulatory DNA in the genome. Creating complete maps of human regulatory DNA is of the utmost importance for understanding genome function, and how this function goes awry in disease.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Specialized Center--Cooperative Agreements (U54)
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Study Section
Special Emphasis Panel (ZHG1-HGR-M (M1))
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Feingold, Elise A
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University of Washington
Schools of Medicine
United States
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Hnisz, Denes; Weintraub, Abraham S; Day, Daniel S et al. (2016) Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351:1454-8
Valton, Anne-Laure; Dekker, Job (2016) TAD disruption as oncogenic driver. Curr Opin Genet Dev 36:34-40
McGeachie, Michael J; Yates, Katherine P; Zhou, Xiaobo et al. (2016) Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma. N Engl J Med 374:1842-52
Vierstra, Jeff; Stamatoyannopoulos, John A (2016) Genomic footprinting. Nat Methods 13:213-21
Hartman, Matthew E; Dai, Dao-Fu; Laflamme, Michael A (2016) Human pluripotent stem cells: Prospects and challenges as a source of cardiomyocytes for in vitro modeling and cell-based cardiac repair. Adv Drug Deliv Rev 96:3-17
Dekker, Job; Mirny, Leonid (2016) The 3D Genome as Moderator of Chromosomal Communication. Cell 164:1110-21
Smith, Emily M; Lajoie, Bryan R; Jain, Gaurav et al. (2016) Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus. Am J Hum Genet 98:185-201
Wang, Xindan; Le, Tung B K; Lajoie, Bryan R et al. (2015) Condensin promotes the juxtaposition of DNA flanking its loading site in Bacillus subtilis. Genes Dev 29:1661-75
Lajoie, Bryan R; Dekker, Job; Kaplan, Noam (2015) The Hitchhiker's guide to Hi-C analysis: practical guidelines. Methods 72:65-75
Mayer, Andreas; di Iulio, Julia; Maleri, Seth et al. (2015) Native elongating transcript sequencing reveals human transcriptional activity at nucleotide resolution. Cell 161:541-54

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