Review Article | Published:

Single-cell epigenomics: techniques and emerging applications

Nature Reviews Genetics volume 16, pages 716726 (2015) | Download Citation


Epigenomics is the study of the physical modifications, associations and conformations of genomic DNA sequences, with the aim of linking these with epigenetic memory, cellular identity and tissue-specific functions. While current techniques in the field are characterizing the average epigenomic features across large cell ensembles, the increasing interest in the epigenetics within complex and heterogeneous tissues is driving the development of single-cell epigenomics. We review emerging single-cell methods for capturing DNA methylation, chromatin accessibility, histone modifications, chromosome conformation and replication dynamics. Together, these techniques are rapidly becoming a powerful tool in studies of cellular plasticity and diversity, as seen in stem cells and cancer.

Key points

  • Single-cell epigenomics combines sensitive epigenetic profiling, single-cell isolation and barcoding and high-throughput sequencing to define epigenetic landscapes across cohorts of single cells.

  • Single-cell bisulfite sequencing characterizes the methylation landscapes of rare and/or heterogeneous cell populations.

  • Single-cell ATAC-seq (assay for transposase-accessible chromatin with high-throughput sequencing) and single-cell Hi-C allow characterization of the variability in local and global physical properties of single chromosomes.

  • Partial epigenomic coverage per single cell can be compensated by increasing sample size, by computational imputation of missing values or by using reference-population epigenomics to assess epigenetic distributions in predefined groups of loci.

  • Integration of single-cell epigenomics with single-cell RNA sequencing (RNA-seq) can be approached in silico by parallel modelling of mixed cell populations at the transcriptional and epigenetic level. Experimental approaches for simultaneous transcriptional and epigenomic profiling at the single-cell level are still under development.

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Research in the A.T. group is supported by the European Research Council, the Israel Science Foundation and the Flight Attendant Medical Research Institute. Work by O.S. was done as part of the requirements for Ph.D. theses at Tel Aviv University.

Author information


  1. Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.

    • Omer Schwartzman
  2. Functional Genomics and Childhood Leukemia Research Section, Cancer Research Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat-Gan 52621, Israel.

    • Omer Schwartzman
  3. Department of Computer Science and Applied Mathematics, and Department of Biological Regulation, Weizmann Institute, Rehovot 7610001, Israel.

    • Omer Schwartzman
    •  & Amos Tanay


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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Amos Tanay.


DNase-hypersensitivity mapping

An assay used to study active regulatory elements in the genome based on their association with regions of low nucleosome density. Owing to reduced protection from nucleosomes, such regions are more sensitive to DNase I-mediated cleavage. Tags of DNA derived from the cleaved chromatin are used to map these regions across the genome.


(Assay for transposase-accessible chromatin with high-throughput sequencing). Similarly to DNase- hypersensitivity mapping, this method is used to identify active regulatory sites characterized by lower density of nucleosomes. It uses the Tn5 transposase, which owing to steric hindrance can insert sequencing adaptor sequences only into regions free of nucleosomes.

Chromatin conformation capture

(3C). An assay for studying chromosomal three-dimensional structure by proximity ligation. The assay relies on crosslinking chromatin with a fixing agent (usually formaldehyde), digestion of the DNA with a six-base or four-base cutter restriction enzyme and, finally, ligation of the fixed chromatin. In the resulting chimeric DNA template, regions that were close spatially are now closed linearly.


A chromatin conformation capture (3C)-based method for genome-wide analysis of chromosome conformation. Hi-C involves deep sequencing of chimeric 3C DNA templates and subsequent statistical analysis of the distribution of ligation junctions over two-dimensional contact matrices. Ultra-deep sequencing, or variants of Hi-C that involve enrichment for specific regions of interest, can be used to enhance the assay's resolution.

DNA-replication domains

In mammals, these are large (1 Mb) genomic regions that consistently replicate at specific stages during S phase. Early replicating domains are strongly correlated with transcriptional activity, whereas late-replicating domains are enriched at the nuclear periphery.

Lamina-associated domains

Regions of chromatin that are in physical proximity to the nuclear envelope. These regions are usually enriched for repressed genes and heterochromatin.

Bisulfite sequencing

An assay to study 5-methylcytosine DNA methylation. Native DNA is exposed to bisulfite. Unmethylated cytosines undergo deamination and are converted to uracils, which are read as thymines, whereas methylated cytosines remain unconverted. Sequencing libraries are generated from the converted template and they allow the study of methylation at single-base resolution.

Unique molecular identifiers

(UMIs). Random or pre-designed short nucleotide sequences that are incorporated into template DNA before PCR amplification. These tags can be used to control for amplification biases.

Reduced-representation bisulfite sequencing

(RRBS). An enrichment-based bisulfite sequencing method. Digestion of the template DNA with a methylation-insensitive restriction enzyme (MspI) is followed by library construction, selection of a narrow range of DNA fragment sizes, bisulfite conversion and sequencing. This results in over tenfold enrichment for CpG-rich genomic sequences, thereby reducing the sequencing requirement in DNA methylation studies.

Post-bisulfite adaptor tagging

(PBAT). A technique for generating bisulfite sequencing libraries. DNA is first treated with bisulfite and then tagged with sequencing adaptors using random priming of the template. This method is simpler and potentially more efficient than other schemes for constructing bisulfite sequencing libraries.


The epigenomic markup of the two copies of each chromosome in a diploid cell. The two epi-haplotypes within a single cell are controlled by the same trans-factors and are therefore expected to be correlated. Nevertheless, regulated and stochastic allele-specific regulation can diversify epi-haplotypes substantially.

Batch effects

Components of technical experimental variation that are associated with the experimental batch but not with other known factors. The degree of batch bias depends on the assay type, along with other technical factors that are difficult to eliminate, such as reagent lots, equipment use and laboratory personnel.

Unsupervised clustering

Grouping of elements (such as single cells or genomic loci) based only on their intrinsic data features and without using external knowledge or assumptions. Several common algorithms for unsupervised clustering differ in their metrics for evaluation of high-quality solutions or in whether they impose a hierarchical structure on the clustered elements.


A range of techniques used to map DNA bound by proteins.

Nucleosome occupancy and methylome sequencing

(NOMe-seq). A footprinting technique in which nuclei are treated with a GpC DNA methyltransferase. Subsequent bisulfite treatment and DNA sequencing can simultaneously reveal DNA regions bound by nucleosomes or other proteins (based on protection from GpC methylation) as well as endogenous DNA methylation at CpG sites.

DNA fluorescence in situ hybridization

(DNA-FISH). A technique to localize specific loci or small groups of loci in nuclei. Fluorescent probes bind specifically to DNA and their visualization allows quantification of the intra-nuclear distances between chromosomal elements in fixed nuclei.

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