The degree to which DNA in a cell is physically open for proteins to bind and regulate genes.Chromatin accessibility describes how reachable a stretch of DNA is to the proteins that read and regulate it. In a cell, DNA is not bare: it is wound around proteins called histones, forming a fibre known as chromatin. Where the fibre is packed tightly, the DNA is largely hidden and the machinery that switches genes on cannot easily get to it. Where the fibre is loose, the DNA is exposed and regulatory proteins can bind. Accessibility is therefore a measure of openness, not of whether a gene is actually switched on — but the two are closely linked, because a gene that cannot be reached cannot easily be activated.
This matters because the same genome is present in every cell of the body, yet a liver cell and a neuron behave very differently. Much of that difference comes down to which regions of the genome are open in each cell type. Regulatory elements such as promoters and enhancers sit in open regions; when a cell changes its identity or responds to a signal, the pattern of open regions changes too. Accessibility is thus one of the main layers of gene regulation, sitting between the raw DNA sequence and the final set of proteins a cell makes.
Measuring accessibility across the whole genome gives a map of which parts of the DNA are in use in a given sample. Comparing maps between healthy and diseased tissue, or between different cell types, reveals which regulatory regions are active and which transcription factors are likely to be working there. This has made chromatin accessibility a standard readout in studies of development, cancer and cell identity.
The idea that chromatin structure controls gene activity goes back to the mid-twentieth century, when researchers noticed that tightly packed regions of the nucleus were transcriptionally quiet. The DNase hypersensitivity assay, developed in the 1970s, was the first practical way to locate open regions. The ATAC-seq method, which made genome-wide accessibility mapping fast and cheap, was introduced by Buenrostro and colleagues in 2013.
The openness of chromatin is controlled by two main mechanisms. First, proteins called transcription factors and the enzyme complexes that copy DNA into RNA can only bind DNA that is not wrapped tightly around histones, so the physical state of the fibre sets a barrier. Second, specialised enzymes can slide, remove or chemically modify histones to open or close specific regions. Adding acetyl groups to histones generally loosens the fibre; adding methyl groups can either loosen or tighten it depending on the site. Cells use these modifications to open regions they need and keep others shut.
Experimentally, accessibility is measured by exploiting the fact that enzymes can cut or tag exposed DNA but not DNA buried in chromatin. In the common assay known as ATAC-seq, a transposase enzyme inserts sequencing tags into open regions of the genome; the tagged fragments are then sequenced, and the number of reads at each position indicates how accessible that region was. Other methods use enzymes that cut DNA, such as DNase, in a similar way. The result is a genome-wide profile of open and closed regions for the sample.
Used to map regulatory elements across cell types, to identify which transcription factors drive a given cell state, and to compare open regions in healthy versus diseased tissue in cancer and developmental research.
Only a small fraction of the human genome — often a few per cent — is accessible in any given cell type at any moment, so the openness map is a strong fingerprint of cell identity.