Editors' ChoiceImmunology

Dendritic cells shaken to the core by pathogenic bacteria

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Science Translational Medicine  14 Oct 2015:
Vol. 7, Issue 309, pp. 309ec175
DOI: 10.1126/scitranslmed.aad4445

Dendritic cells (DCs) propagate the immune response, traveling from damaged and/or infected tissues to lymphoid organs, where they instruct adaptive immune cells—namely, T cells and B cells—to confront infection and injury. When DCs encounter pathogens, they “mature,” a process involving a rapid, coordinated induction of a transcriptional program necessary for antigen presentation and expression of costimulatory molecules. Decades of research have taught us about the key transcription factors and downstream genes involved in DC maturation. Now, Pacis et al. provide a comprehensive look at the epigenetic reprogramming that accompanies and likely governs these gene expression changes.

DNA methylation generally restricts the transcriptional potential of nearby genes in a manner historically thought to be quite stable. However, this new research shows us that DNA methylation can be actively removed in postmitotic DCs in response to infection; this was demonstrated experimentally with ambitious, genome-wide characterization of DNA methylation (using MethylC-seq) in monocyte-derived DCs before and after exposure to live pathogenic Mycobacterium tuberculosis (MTB).

The sites hypomethylated following MTB exposure were occasionally in gene promoter regions, but were mostly found in highly conserved, more distant enhancer elements. Particularly remarkable was that just over 10% were in previously heterochromatic regions of the genome, which are notoriously transcriptionally silent. Hypomethylated sites were not random or genome-wide, but specific and in strategic proximity to genes known to be master regulators of immune responses (such as NF-KB/REL and IRFs). Through ChIP-seq experiments for histone modifications characteristic of chromatin state (for example repressed, active, poised), the authors showed that newly hypomethylated sites also gained activating marks that promote transcription. The temporal dynamics of the DNA methylation changes after pathogen exposure are intriguing: Hypomethylated regions looked primed for derepression even before infection, already enriched in 5-hydroxymethyl cytosine (the intermediate en route to demethylation). Also, the timing of decreasing DNA methylation at some of the loci was too slow relative to induction of gene expression for this to be required for gene up-regulation, but the modified DNA importantly persisted, highlighting a potential mechanism for DCs’ newly appreciated capacity for “memory.”

In addition to providing a genome-wide epigenetic and gene expression map of a DC response to MTB, which is a valuable resource as we try to understand cellular response to infection, this work provides a framework from which we can learn about pathogen-specific versus generic responses. The translational impact of this work relies on further development of targeted therapies against the enzymes implicated in DNA (de)methylation (such as DNA methyltransferases, TET proteins), but there are numerous diseases attributable to insufficient or inappropriate DC behavior that could benefit from tinkering with these cells.

A. Pacis et al., Bacterial infection remodels the DNA methylation landscape of human dendritic cells. Genome Res. 10.1101/gr.192005.115 (2015). [Abstract]

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