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Nat Commun. 2015 Jun 15;6:7438. doi: 10.1038/ncomms8438.

Single molecule-level detection and long read-based phasing of epigenetic variations in bacterial methylomes.

Author information

1
Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
2
Department of Medicine, New York University School of Medicine, New York 10016, USA.
3
Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, and the Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.

Abstract

Beyond its role in host defense, bacterial DNA methylation also plays important roles in the regulation of gene expression, virulence and antibiotic resistance. Bacterial cells in a clonal population can generate epigenetic heterogeneity to increase population-level phenotypic plasticity. Single molecule, real-time (SMRT) sequencing enables the detection of N6-methyladenine and N4-methylcytosine, two major types of DNA modifications comprising the bacterial methylome. However, existing SMRT sequencing-based methods for studying bacterial methylomes rely on a population-level consensus that lacks the single-cell resolution required to observe epigenetic heterogeneity. Here, we present SMALR (single-molecule modification analysis of long reads), a novel framework for single molecule-level detection and phasing of DNA methylation. Using seven bacterial strains, we show that SMALR yields significantly improved resolution and reveals distinct types of epigenetic heterogeneity. SMALR is a powerful new tool that enables de novo detection of epigenetic heterogeneity and empowers investigation of its functions in bacterial populations.

PMID:
26074426
PMCID:
PMC4490391
DOI:
10.1038/ncomms8438
[Indexed for MEDLINE]
Free PMC Article

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