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

John Beaulaurier, Xue-Song Zhang, Shijia Zhu, Robert Sebra, Chaggai Rosenbluh, Gintaras Deikus, Nan Shen, Diana Munera, Matthew K. Waldor, Andrew Chess, Martin J. Blaser, Eric E. Schadt () and Gang Fang ()
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John Beaulaurier: Icahn School of Medicine at Mount Sinai
Xue-Song Zhang: New York University School of Medicine
Shijia Zhu: Icahn School of Medicine at Mount Sinai
Robert Sebra: Icahn School of Medicine at Mount Sinai
Chaggai Rosenbluh: Icahn School of Medicine at Mount Sinai
Gintaras Deikus: Icahn School of Medicine at Mount Sinai
Nan Shen: Icahn School of Medicine at Mount Sinai
Diana Munera: Brigham and Women’s Hospital, Harvard Medical School, and the Howard Hughes Medical Institute
Matthew K. Waldor: Brigham and Women’s Hospital, Harvard Medical School, and the Howard Hughes Medical Institute
Andrew Chess: Icahn School of Medicine at Mount Sinai
Martin J. Blaser: New York University School of Medicine
Eric E. Schadt: Icahn School of Medicine at Mount Sinai
Gang Fang: Icahn School of Medicine at Mount Sinai

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8438

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