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Deciphering bacterial epigenomes using modern sequencing technologies

Nature Reviews Geneticsvolume 20pages157172 (2019) | Download Citation


Prokaryotic DNA contains three types of methylation: N6-methyladenine, N4-methylcytosine and 5-methylcytosine. The lack of tools to analyse the frequency and distribution of methylated residues in bacterial genomes has prevented a full understanding of their functions. Now, advances in DNA sequencing technology, including single-molecule, real-time sequencing and nanopore-based sequencing, have provided new opportunities for systematic detection of all three forms of methylated DNA at a genome-wide scale and offer unprecedented opportunities for achieving a more complete understanding of bacterial epigenomes. Indeed, as the number of mapped bacterial methylomes approaches 2,000, increasing evidence supports roles for methylation in regulation of gene expression, virulence and pathogen–host interactions.

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The authors thank A. Tourancheau and other members of the Fang laboratory for their comments. The work was funded by R01 GM114472 (G.F.) and R01 GM128955 (G.F.) from the National Institutes of Health. G.F. is an Irma T. Hirschl/Monique Weill-Caulier Trust Research Scholar and a Nash Family Research Scholar.

Reviewer information

Nature Reviews Genetics thanks J. Casadesus, M. Oggioni and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • John Beaulaurier
    • , Eric E. Schadt
    •  & Gang Fang


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All authors researched data for the article, made substantial contributions to discussions of the content and reviewed and/or edited the manuscript before submission. J.B. and G.F. wrote the article.

Competing interests

J.B. is currently employed by Oxford Nanopore Technologies, Ltd. G.F. and E.S. declare no competing interests.

Corresponding author

Correspondence to Gang Fang.


Phase variation

A means by which reversible variation of protein expression is achieved in bacteria, often in an ON/OFF manner. The process creates phenotypic diversity in a clonally expanded population and allows the colony to survive in rapidly changing environments.

Adaptive selection

An evolutionary process though which surviving organisms accumulate genetic changes that lead to a fitness advantage over their progenitors.


The entirety of DNA methylation marks across genomes.

Bisulfite sequencing

The treatment of DNA with bisulfite chemically converts unmethylated cytosines to uracils. As methylated cytosines are unaffected, the location of methylation can be identified by sequencing the bisulfite-treated DNA.

Hidden Markov model

(HMM). A mathematical concept that describes a finite set of ‘states’ and a probabilistic model for transitioning from one state to another. The probability associated with each transition can be derived from training sets. HMMs are valuable because they enable a search or alignment algorithm to be built on firm probabilistic bases.

Hierarchical Dirichlet process

(HDP). A non-parametric Bayesian approach for modelling a collection of mixture distributions that share mixture components.

Chromatin conformation capture

A technique used to assess the spatial organization of chromosomes within a cell. Briefly, DNA is first chemically crosslinked and fragmented. The crosslinked fragments are then ligated. When sequenced, the ligated fragments produce concatemers that help reveal which regions of sequence co-locate within the cell.

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