The accessible chromatin landscape of the human genome.
Nature. 2012 Sep 6;489(7414):75-82.
- Abstract
- 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 approximately 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 approximately 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.
- References
Related data
- Available data
- promoter regions
- Data summary
- For a given cell-type, we compute the 20th percentile D of the mean H3K4me3 density over a 550 bp window around Gencode v7 promoters overlapping a DHS from that cell-type. Within the set of promoters overlapping DHSs at the 20th percentile or greater for mean H3K4me3 signal, we look at the ratio of the H3K4me3 signal flanking the DHS to the signal at the DHS. More specifically, for each selected promoter, we compute the mean H3K4me3 signal over the 150 bp promoter DHS; over the 200 bp window immediately to the left of the DHS; and over the 200 bp immediately to the right of the DHS. For each flank we then compute the ratio of the flanking mean to the DHS mean, and retain the greater of these two ratios. We then find the 20th percentile across all selected promoters of these maximum ratios, R. To identify the “promoter DHS” from the pool of all DHSs within the given cell-type, we next find all DHSs that have mean 550 bp windowed (centered on the DHS) H3K4me3 density greater than or equalt to D. Within that set of DHSs, we flag all those that have ratio R(prime) greater than or equal to R, where R(prime) is the greater of the ratios of the mean H3K4me3 density in either of the flanking 200bp windows to the mean H3K4me3 density over the DHS. Note that the flanking window that gives the greater ratio also gives the prediction of the direction of the promoter.
- Available data
- connectivity
- Data summary
- 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. We connect ∼580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types.