DNaseI hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers, and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ~2.9 million DHSs that encompass virtually all known experimentally-validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation, and regulatory factor occupancy patterns. We connect ~580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is choreographed with dozens to hundreds of co-activated elements, and the trans-cellular DNaseI sensitivity pattern at a given region can predict cell type-specific functional behaviors. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms correspondence: jstam@uw.edu. *these authors contributed equally Author Contributions Generation of DNaseI data was supervised by J.A.S. and G.E.C., with data collection carried out by D.B., T.K.C., R.S.H., M.D., D.D., E.G., T.K., K.L., F.N., V.R., A.S. (UW), S.V., M.W., B-K.L., D.L., A.S., L.S., Z.Z, and Z.Z. (Duke). 5C experiments were supervised by J.D. and performed by A.S. (UMass). Primary DNaseI data processing was performed by R.S., T.S.F., A.K.J., and A.P.R. Hypersensitivity Southerns and Enhancer cloning and transfection experiments were performed by E.M.J., A.K.E., T.F., E.D.N., L.H., and M.S.and supervised by P.A.N. and G.S. H3K4me3 ChIP-seq experiments were performed by H.W. Primary analysis of DNaseI data was performed by R.E.T., R.S., and R.H. Joint analysis of DNaseI and transcription factor ChIP-seq data was performed by J.V. and A.B.S. Promoter prediction analysis was performed by R.E.T. DNaseI vs. DNA methylation analysis was performed by M.T.M. DHS-promoter connectivity analysis was performed by E.R. Integration of DNaseI and 5C data was performed by R.H. with assistance from B.L. (UMass). DHS stereotyping pattern analysis was performed by E.H. Self-organizing map analysis was performed by N.S. and B.L. (Bergen). Variation analysis was performed by B.V. and E.R. under direction of S.S., J.M.A., and J.A.S. Data interpretation and figure design were performed by J.A.S., R.E.T., J.D.L., V.R.I., G.E.C., and T.S.F. J.A.S., R.E.T., E.R., R.H., J.V., M.T.M., A.B.S., and N.S. wrote the paper. Competing Interests The authors declare no competing interests. Data Availability DNaseI-seq data are available through the UCSC browser, and through the NCBI Gene Expression Omnibus (GEO) data repository under accessions GSE29692, GSE32970. H3K4me3 and 5C data are available through the UCSC browser, and through the NCBI Gene Expression Omnibus (GEO) data repository. Gene expression data are available through the UCSC browser, and through the NCBI Gene Expression Omnibus (GEO) data repository under accessions GSE19090, GSE15805, GSE17778. HHS Public Access Author manuscript Nature. Author manuscript; available in PMC 2013 July 24. Published in final edited form as: Nature. 2012 September 6; 489(7414): 75–82. doi:10.1038/nature11232. A uhor M anscript
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