Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity

doi:10.1186/s13059-016-0944-x

Review

. 2016 Apr 18:17:72.

doi: 10.1186/s13059-016-0944-x.

Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity

Stephen J Clark¹, Heather J Lee^{2

3}, Sébastien A Smallwood^{1

4}, Gavin Kelsey^{1

5}, Wolf Reik^{1

6

5

7}

Affiliations

¹ Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK.
² Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK. heather.lee@babraham.ac.uk.
³ Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK. heather.lee@babraham.ac.uk.
⁴ Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH 4058, Basel, Switzerland.
⁵ Centre for Trophoblast Research, University of Cambridge, Cambridge, CB2 3EG, UK.
⁶ Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
⁷ Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK.

PMID: 27091476
PMCID: PMC4834828
DOI: 10.1186/s13059-016-0944-x

Review

Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity

Stephen J Clark et al. Genome Biol. 2016.

. 2016 Apr 18:17:72.

doi: 10.1186/s13059-016-0944-x.

Authors

Stephen J Clark¹, Heather J Lee^{2

3}, Sébastien A Smallwood^{1

4}, Gavin Kelsey^{1

5}, Wolf Reik^{1

6

5

7}

Affiliations

¹ Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK.
² Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK. heather.lee@babraham.ac.uk.
³ Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK. heather.lee@babraham.ac.uk.
⁴ Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH 4058, Basel, Switzerland.
⁵ Centre for Trophoblast Research, University of Cambridge, Cambridge, CB2 3EG, UK.
⁶ Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
⁷ Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK.

PMID: 27091476
PMCID: PMC4834828
DOI: 10.1186/s13059-016-0944-x

Abstract

Emerging single-cell epigenomic methods are being developed with the exciting potential to transform our knowledge of gene regulation. Here we review available techniques and future possibilities, arguing that the full potential of single-cell epigenetic studies will be realized through parallel profiling of genomic, transcriptional, and epigenetic information.

PubMed Disclaimer

Figures

**Fig. 1**
Epigenomics and the spectrum of single-cell sequencing technologies. The diagram outlines the single-cell sequencing technologies currently available. A single cell is first isolated by means of droplet encapsulation, manual manipulation, fluorescence-activated cell sorting (*FACS*) or microfluidic processing. The first examples of single-cell multi-omic technologies have used parallel amplification or physical separation to measure gene expression (*scRNA-seq*) and DNA sequence (*scDNA-seq*) from the same cell. Note that single-cell bisulfite conversion followed by sequencing (*scBS-seq*) is not compatible with parallel amplification of RNA and DNA, as DNA methylation is not conserved during in vitro amplification. Single-cell epigenomics approaches utilize chemical treatment of DNA (bisulfite conversion), immunoprecipitation or enzymatic digest (e.g., by DNaseI) to study DNA modifications (*scBS-seq* and *scRRBS*), histone modifications (*scChIP-seq*), DNA accessibility (*scATAC-seq*, *scDNase-seq*), chromatin conformation (*scDamID, scHiC*)

**Fig. 2**
Future applications of single-cell epigenomics. The full potential of emerging single-cell epigenomic techniques will be realized through integration with transcriptome and genome sequencing. Single-cell multi-omics will be applied to biological questions involving the molecular mechanisms of epigenetic regulation (e.g., the functional consequences of rare DNA modifications), intercellular heterogeneity, and rare cell types (e.g., in early development). *scATAC-seq* single cell assay for transposase-accessible chromatin, *scBS-seq* single-cell bisulfite sequencing, *scChIP-seq* single-cell chromatin immunoprecipitation followed by sequencing, *scDNase-seq* single-cell DNase sequencing, *scHiC* single-cell HiC, *scRRBS* single-cell reduced representation bisulfite sequencing

See this image and copyright information in PMC

Cited by

Opportunities and Challenges in Advancing Plant Research with Single-cell Omics.
Rhaman MS, Ali M, Ye W, Li B. Rhaman MS, et al. Genomics Proteomics Bioinformatics. 2024 Jul 3;22(2):qzae026. doi: 10.1093/gpbjnl/qzae026. Genomics Proteomics Bioinformatics. 2024. PMID: 38996445 Free PMC article. Review.
Network Approaches for Dissecting the Immune System.
Hao Shi, Yan KK, Ding L, Qian C, Chi H, Yu J. Hao Shi, et al. iScience. 2020 Aug 21;23(8):101354. doi: 10.1016/j.isci.2020.101354. Epub 2020 Jul 10. iScience. 2020. PMID: 32717640 Free PMC article. Review.
Joint reconstruction of cis-regulatory interaction networks across multiple tissues using single-cell chromatin accessibility data.
Dong K, Zhang S. Dong K, et al. Brief Bioinform. 2021 May 20;22(3):bbaa120. doi: 10.1093/bib/bbaa120. Brief Bioinform. 2021. PMID: 32578841 Free PMC article.
The Kaleidoscope of Microglial Phenotypes.
Dubbelaar ML, Kracht L, Eggen BJL, Boddeke EWGM. Dubbelaar ML, et al. Front Immunol. 2018 Jul 31;9:1753. doi: 10.3389/fimmu.2018.01753. eCollection 2018. Front Immunol. 2018. PMID: 30108586 Free PMC article. Review.
DNA methylation clocks tick in naked mole rats but queens age more slowly than nonbreeders.
Horvath S, Haghani A, Macoretta N, Ablaeva J, Zoller JA, Li CZ, Zhang J, Takasugi M, Zhao Y, Rydkina E, Zhang Z, Emmrich S, Raj K, Seluanov A, Faulkes CG, Gorbunova V. Horvath S, et al. Nat Aging. 2022 Jan;2(1):46-59. doi: 10.1038/s43587-021-00152-1. Epub 2021 Dec 23. Nat Aging. 2022. PMID: 35368774 Free PMC article.

See all "Cited by" articles

References

1. Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007;128:669–81. doi: 10.1016/j.cell.2007.01.033. - DOI - PubMed
1. Macaulay IC, Voet T. Single cell genomics. Advances and future perspectives. PLoS Genet. 2014;10:e1004126. doi: 10.1371/journal.pgen.1004126. - DOI - PMC - PubMed
1. Brunner AL, Johnson DS, Kim SW, Valouev A, Reddy TE, Neff NF, et al. Distinct DNA methylation patterns characterize differentiated human embryonic stem cells and developing human fetal liver. Genome Res. 2009;19:1044–56. doi: 10.1101/gr.088773.108. - DOI - PMC - PubMed
1. Down TA, Rakyan VK, Turner DJ, Flicek P, Li H, Kulesha E, et al. A Bayesian deconvolution strategy for immunoprecipitation-based DNA methylome analysis. Nat Biotechnol. 2008;26:779–85. doi: 10.1038/nbt1414. - DOI - PMC - PubMed
1. Cokus SJ, Feng S, Zhang X, Chen Z, Merriman B, Haudenschild CD, et al. Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning. Nature. 2008;452:215–9. doi: 10.1038/nature06745. - DOI - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations

[1] Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007;128:669–81. doi: 10.1016/j.cell.2007.01.033. - DOI - PubMed

[2] Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007;128:669–81. doi: 10.1016/j.cell.2007.01.033. - DOI - PubMed

[3] Macaulay IC, Voet T. Single cell genomics. Advances and future perspectives. PLoS Genet. 2014;10:e1004126. doi: 10.1371/journal.pgen.1004126. - DOI - PMC - PubMed

[4] Macaulay IC, Voet T. Single cell genomics. Advances and future perspectives. PLoS Genet. 2014;10:e1004126. doi: 10.1371/journal.pgen.1004126. - DOI - PMC - PubMed

[5] Brunner AL, Johnson DS, Kim SW, Valouev A, Reddy TE, Neff NF, et al. Distinct DNA methylation patterns characterize differentiated human embryonic stem cells and developing human fetal liver. Genome Res. 2009;19:1044–56. doi: 10.1101/gr.088773.108. - DOI - PMC - PubMed

[6] Brunner AL, Johnson DS, Kim SW, Valouev A, Reddy TE, Neff NF, et al. Distinct DNA methylation patterns characterize differentiated human embryonic stem cells and developing human fetal liver. Genome Res. 2009;19:1044–56. doi: 10.1101/gr.088773.108. - DOI - PMC - PubMed

[7] Down TA, Rakyan VK, Turner DJ, Flicek P, Li H, Kulesha E, et al. A Bayesian deconvolution strategy for immunoprecipitation-based DNA methylome analysis. Nat Biotechnol. 2008;26:779–85. doi: 10.1038/nbt1414. - DOI - PMC - PubMed

[8] Down TA, Rakyan VK, Turner DJ, Flicek P, Li H, Kulesha E, et al. A Bayesian deconvolution strategy for immunoprecipitation-based DNA methylome analysis. Nat Biotechnol. 2008;26:779–85. doi: 10.1038/nbt1414. - DOI - PMC - PubMed

[9] Cokus SJ, Feng S, Zhang X, Chen Z, Merriman B, Haudenschild CD, et al. Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning. Nature. 2008;452:215–9. doi: 10.1038/nature06745. - DOI - PMC - PubMed

[10] Cokus SJ, Feng S, Zhang X, Chen Z, Merriman B, Haudenschild CD, et al. Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning. Nature. 2008;452:215–9. doi: 10.1038/nature06745. - DOI - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity

Affiliations

Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity

Authors

Affiliations

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources