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EPIGENETICS

Chromatin accessibility and the regulatory epigenome

Abstract

Physical access to DNA is a highly dynamic property of chromatin that plays an essential role in establishing and maintaining cellular identity. The organization of accessible chromatin across the genome reflects a network of permissible physical interactions through which enhancers, promoters, insulators and chromatin-binding factors cooperatively regulate gene expression. This landscape of accessibility changes dynamically in response to both external stimuli and developmental cues, and emerging evidence suggests that homeostatic maintenance of accessibility is itself dynamically regulated through a competitive interplay between chromatin-binding factors and nucleosomes. In this Review, we examine how the accessible genome is measured and explore the role of transcription factors in initiating accessibility remodelling; our goal is to illustrate how chromatin accessibility defines regulatory elements within the genome and how these epigenetic features are dynamically established to control gene expression.

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Fig. 1: A continuum of accessibility states broadly reflects the distribution of chromatin dynamics across the genome.
Fig. 2: Principal methods for measuring chromatin accessibility.
Fig. 3: Population-scale measurements of chromatin accessibility reflect the average accessibility of a heterogeneous collection of single molecules.
Fig. 4: Nucleosome turnover and occupancy are inversely correlated across a broad range of genomic regions.
Fig. 5: Models of chromatin accessibility remodelling.

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Acknowledgements

The authors thank M. Moria-Shipony for graphics assistance as well as A. Koh, V. Risca, G. Marinov, N. Sinnott-Armstrong and A. Trevino for critical feedback on this manuscript. This work was supported by the NIH (P50HG007735, UM1HG009442, U19AI057266 and 1UM1HG009436), the Rita Allen Foundation, the Baxter Foundation Faculty Scholar Grant and the Human Frontiers Science Program grant RGY006S. W.J.G is a Chan Zuckerberg Biohub investigator and acknowledges grants 2017-174468 and 2018-182817 from the Chan Zuckerberg Initiative. Z.S. is supported by grants EMBO ALTF 1119-2016 and HFSP LT 000835/2017-L. S.K. has received support from a Ruth L. Kirschstein Institutional National Research Service Award (NRSA, NIH 5 T32 HG000044).

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Nature Reviews Genetics thanks D. Gifford, K. Rippe and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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S.L.K., Z.S. and W.J.G. conceived and wrote the manuscript.

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Correspondence to William J. Greenleaf.

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W.J.G. is a co-founder of Epinomics and an adviser to 10X Genomics, Guardant Health and Centrillion.

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Related links

10X Genomics single-cell ATAC-seq: https://www.10xgenomics.com/solutions/single-cell-atac/

Bio-Rad Laboratories single-cell ATAC-seq: http://www.bio-rad.com/scATAC-Seq

Glossary

Chromatin-binding factors

Non-histone macromolecules that bind either directly or indirectly to DNA.

Transcription factor

(TF). A non-histone protein that directly binds to DNA.

Architectural proteins

Proteins that have a structural role in organizing chromatin, including linker and core histone proteins, as well as insulator proteins.

Nucleosome occupancy

The fraction of time that a particular sequence of DNA is bound by the core histone octamer.

Epigenetic canalization

A set of persistent epigenetic features (alternatively, the process of establishing this feature set) that molecularly defines a cell type and comprises a continuum of cellular states including cell cycle phases and activation states.

TF footprinting

High-resolution analysis of chromatin accessibility data to identify a local accessibility signature in the neighbourhood of putative binding sites for a particular transcription factor (TF). This signature reflects the size and binding mechanism, as well as other biophysical properties, of a TF.

Nucleosome turnover rates

The rates at which nucleosomes disassemble at particular genomic loci; alternatively, the inverse of the nucleosome residence times.

Poised enhancers

Inactive enhancers that do not regulate gene expression but share a subset of epigenetic features commonly observed at active enhancers, including histone H3 lysine 4 monomethylation (H3K4me)and accessibility.

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Klemm, S.L., Shipony, Z. & Greenleaf, W.J. Chromatin accessibility and the regulatory epigenome. Nat Rev Genet 20, 207–220 (2019). https://doi.org/10.1038/s41576-018-0089-8

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