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The epigenetic basis of cellular heterogeneity

Nature Reviews Genetics volume 22, pages 235–250 (2021)Cite this article

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Abstract

Single-cell sequencing-based methods for profiling gene transcript levels have revealed substantial heterogeneity in expression levels among morphologically indistinguishable cells. This variability has important functional implications for tissue biology and disease states such as cancer. Mapping of epigenomic information such as chromatin accessibility, nucleosome positioning, histone tail modifications and enhancer–promoter interactions in both bulk-cell and single-cell samples has shown that these characteristics of chromatin state contribute to expression or repression of associated genes. Advances in single-cell epigenomic profiling methods are enabling high-resolution mapping of chromatin states in individual cells. Recent studies using these techniques provide evidence that variations in different aspects of chromatin organization collectively define gene expression heterogeneity among otherwise highly similar cells.

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Fig. 1: Epigenetic landscapes of transcribed and silent genes in eukaryotes.
Fig. 2: Single-cell techniques provide greater resolution than bulk-cell methods.
Fig. 3: scATAC-seq and scDNase-seq measure the dynamics of accessible chromatin sites.
Fig. 4: scMNase-seq reveals nucleosome positioning dynamics.
Fig. 5: Single-cell Hi-C-based techniques measure the variability of enhancer–promoter contacts.

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Acknowledgements

The research in the authors’ laboratory is supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health.

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  1. Laboratory of Epigenome Biology, Systems Biology Center, NHLBI, NIH, Bethesda, MD, USA

    Benjamin Carter & Keji Zhao

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  1. Benjamin Carter
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The authors contributed equally to all aspects of the article.

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Correspondence to Benjamin Carter or Keji Zhao.

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Glossary

Chromatin

Genomic material found in the cell nucleus comprising DNA in complex with structural proteins such as histones.

Epigenetic marks

Changes in chromatin including covalent modifications of DNA and histones that are persistent and often associated with changes in gene expression.

Chromatin immunoprecipitation followed by sequencing

(ChIP–seq). A commonly used method for profiling epigenetic marks or chromatin binding proteins. The method is based on the affinity of an antibody for its target antigen(s).

Heterochromatic

Pertaining to heterochromatin, which is tightly packaged chromatin that is associated with transcriptional repression and enriched for characteristic epigenetic marks such as trimethylation of lysine 9 at histone 3 (H3K9me3).

Fluorescence-activated cell sorting

A method used to separate and distribute a cellular subpopulation from a larger sample based on fluorescence, typically accomplished via expression of a fluorophore transgene or via labelling with a fluorescent antibody.

Bivalent modifications

Genomic regions exhibiting co-enrichment of epigenetic marks considered to be transcriptionally activating and transcriptionally repressive. In particular, they often refer to dual enrichment of the histone modifications trimethylation of lysine 4 at histone 3 (H3K4me3) and H3K27me3.

Tagmentation

The use of a transposase to fragment DNA and append sequence tags to the resulting fragments in a single experimental step.

Split-pool barcoding

A procedure that uses libraries of sequence tags to obtain information at a single-cell level without the need for sorting of individual cells. This is accomplished by splitting samples into small aliquots, adding a barcode and pooling them. This process is repeated two or three times to ensure that each cell is highly likely to receive a unique combination of barcodes.

Imprinted genes

Genes that exhibit allele-specific or allele-biased expression depending on the parent of origin.

CRISPR–Cas9

A method for genome engineering that is derived from the CRISPR system of antiviral defence in bacteria.

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Carter, B., Zhao, K. The epigenetic basis of cellular heterogeneity. Nat Rev Genet 22, 235–250 (2021). https://doi.org/10.1038/s41576-020-00300-0

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