Bacterial infection remodels the DNA methylation landscape of human dendritic cells

  1. Luis B. Barreiro1,13
  1. 1Department of Genetics, CHU Sainte-Justine Research Center, Montreal, H3T1C5 Canada;
  2. 2Department of Biochemistry, University of Montreal, Montreal, H3T1J4 Canada;
  3. 3Institut Pasteur, Mycobacterial Genetics Unit, Paris, 75015 France;
  4. 4Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T1Z4, Canada;
  5. 5Génome Québec Innovation Centre, Department of Human Genetics, McGill University, Montreal, H3A0G1 Canada;
  6. 6Institut Pasteur, Imagopole, Paris, 75015 France;
  7. 7Center for Molecular Medicine and Genetics and Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan 48202, USA;
  8. 8Department of Biostatistics and McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA;
  9. 9Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois 60637, USA;
  10. 10Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
  11. 11Departments of Evolutionary Anthropology and Biology and Duke Population Research Institute, Duke University, Durham, North Carolina 27708, USA;
  12. 12Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA;
  13. 13Department of Pediatrics, University of Montreal, Montreal, H3T1J4 Canada
  1. Corresponding authors: luis.barreiro{at}umontreal.ca, gilad{at}uchicago.edu

Abstract

DNA methylation is an epigenetic mark thought to be robust to environmental perturbations on a short time scale. Here, we challenge that view by demonstrating that the infection of human dendritic cells (DCs) with a live pathogenic bacteria is associated with rapid and active demethylation at thousands of loci, independent of cell division. We performed an integrated analysis of data on genome-wide DNA methylation, histone mark patterns, chromatin accessibility, and gene expression, before and after infection. We found that infection-induced demethylation rarely occurs at promoter regions and instead localizes to distal enhancer elements, including those that regulate the activation of key immune transcription factors. Active demethylation is associated with extensive epigenetic remodeling, including the gain of histone activation marks and increased chromatin accessibility, and is strongly predictive of changes in the expression levels of nearby genes. Collectively, our observations show that active, rapid changes in DNA methylation in enhancers play a previously unappreciated role in regulating the transcriptional response to infection, even in nonproliferating cells.

Footnotes

  • Received March 10, 2015.
  • Accepted September 17, 2015.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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  1. Published in Advance September 21, 2015, doi: 10.1101/gr.192005.115 Genome Res. 25: 1801-1811 © 2015 Pacis et al.; Published by Cold Spring Harbor Laboratory Press

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