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Edited by Barry R. Bloom, Harvard T. H. Chan School of Public Health, Boston, MA, and approved February 21, 2019 (received for review August 27, 2018)
Significance
Immune response to infection is accompanied by active demethylation of thousands of CpG sites. Yet, the causal relationship between changes in DNA methylation and gene expression during infection remains to be elucidated. Here, we investigated the role of DNA methylation in the regulation of innate immune responses to bacterial infections. We found that virtually all changes in gene expression in response to infection occur prior to detectable alterations in the methylome. We also found that the binding of most infection-induced transcription factors precedes loss of methylation. Collectively, our results show that changes in methylation are a downstream consequence of transcription factor binding, and not essential for the establishment of the core regulatory program engaged upon infection.
Abstract
DNA methylation is considered to be a relatively stable epigenetic mark. However, a growing body of evidence indicates that DNA methylation levels can change rapidly; for example, in innate immune cells facing an infectious agent. Nevertheless, the causal relationship between changes in DNA methylation and gene expression during infection remains to be elucidated. Here, we generated time-course data on DNA methylation, gene expression, and chromatin accessibility patterns during infection of human dendritic cells with Mycobacterium tuberculosis. We found that the immune response to infection is accompanied by active demethylation of thousands of CpG sites overlapping distal enhancer elements. However, virtually all changes in gene expression in response to infection occur before detectable changes in DNA methylation, indicating that the observed losses in methylation are a downstream consequence of transcriptional activation. Footprinting analysis revealed that immune-related transcription factors (TFs), such as NF-κB/Rel, are recruited to enhancer elements before the observed losses in methylation, suggesting that DNA demethylation is mediated by TF binding to cis-acting elements. Collectively, our results show that DNA demethylation plays a limited role to the establishment of the core regulatory program engaged upon infection.
Footnotes
↵1A.P. and F.M.-L. contributed equally to this work.
↵2Present address: Canadian Centre for Computational Genomics, McGill University and Genome Quebec Innovation Center, Montreal, QC H3A0G1, Canada.
- ↵3To whom correspondence should be addressed. Email: lbarreiro{at}uchicago.edu.
Author contributions: L.B.B. designed research; A.P., F.M.-L., L.T., H.E.R., V.Y., A.D., and L.B.B. performed research; L.T. contributed new reagents/analytic tools; A.P. and J.-C.G. analyzed data; and A.P., F.M.-L., and L.B.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: Data generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) under accession numbers GSE116406 (ATAC-seq), GSE116411 (ChIP-seq), GSE116405 (RNA-seq), and GSE116399 (SeqCap Epi).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1814700116/-/DCSupplemental.
- Copyright © 2019 the Author(s). Published by PNAS.
This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Gene activation precedes DNA demethylation in response to infection in human dendritic cells
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