The accessible chromatin landscape of the human genome

By Robert E. Thurman, Eric Rynes, R. Humbert, J. Vierstra, Matthew T. Maurano, E. Haugen, Nathan C. Sheffield, Andrew B. Stergachis, Benjamin Vernot, Kavita S Garg and 48 more. Nature, 2012

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DNase I 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 organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/73061c8a47871944daf7519065930112e06d98e5

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Citations in the corpus

The long-range interaction landscape of gene promoters (2012, background): “Furthermore,5CinteractionfrequenciesarecorrelatedwithTSS– distalDHSpairspredictedtobefunctionallyconnectedbasedontheir highly correlated activity across a large panel of cell lines ( P , 10 2 13 , one-sided Mann–Whitney U -test 17 ), providing independent validation of their biological significance.”
Joint analysis of functional genomic data and genome-wide association studies of 18 human traits (2013, background): “The main sources of genome annotations were 402 maps of DNase-I hypersensitivity in a wide range of primary cell types and cell lines.(11,44) I also included as annotations the output from ‘‘genome segmentation’’ of the six main ENCODE cell lines;(45) for each section of the genome in each cell line”
Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes (2013, neutral): “Between 400,000 and 1.4 million putative enhancers have been identified in the mammalian genome by using a variety of high-throughput techniques that detect features of enhancers such as specific histone modifications (Dunham et al., 2012; Thurman et al., 2012).”
Gene regulatory network inference in the era of single-cell multi-omics (2023, methodology): “In addition, the ENCODE Consortium has catalogued, using various biochemical assays, more than one million candidate CREs with enhancer-like signatures that span ~16% of the human genome 36,122,123 .”
Sequence and chromatin determinants of cell-type–specific transcription factor binding (2012, methodology): “The ENCODE project also provides genome-wide data on chromatin state in many of the same cell lines, including ChIP-seq profiling of histone modifications and DNase-seq assays to profile chromatin accessibility (Ernst et al. 2011; Thurman et al. 2012).”
RNA-Guided Human Genome Engineering via Cas9 (2013, neutral): “As we gather information on CRISPR performance at our computationally predicted human exon CRISPR target sites, we plan to refine our database by correlating performance with factors we expect to ”