Epigenetic regulation of the innate immune response to infection


Innate immune cells have complex signalling pathways for sensing pathogens and initiating innate immune responses against infection. These pathways are tightly regulated at different levels, including by epigenetic regulators. In this Review, we discuss studies revealing the epigenetic mechanisms, as well as the post-transcriptional and post-translational modifications by chromatin modifiers, that underlie the establishment of these signalling networks and the rapid induction of innate immune molecules during infection. We also discuss how pathogens use their own products, as well as host components, to target host epigenomes for immune evasion and survival. We describe the crosstalk between epigenetic regulators and new modulators, such as inflammation-specific metabolites, and how we might deconstruct dynamic chromatin patterns and identify critical chromatin modifiers of host–pathogen interactions.

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Fig. 1: Interplay between epigenetic regulation and innate immunity against infection.
Fig. 2: Epigenetic regulation of signalling pathways during infection.
Fig. 3: Epigenetic regulation of effector molecules that act against infection.
Fig. 4: Crosstalk between cell metabolic pathways and epigenetic regulation in innate immunity.
Fig. 5: Pathogen products directly and indirectly regulate the host epigenome.


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This work was supported by grants from the National Natural Science Foundation of China (81788101) and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2016-I2M-1-003).

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Nature Reviews Immunology thanks S.-C. Sun and other anonymous reviewer(s) for their contribution to the peer review of this work.

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The authors contributed equally to all aspects of the article.

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Correspondence to Qian Zhang or Xuetao Cao.

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CpG islands

(CGIs). Genomic regions of more than 500 nucleotides in length with higher-than-average frequency (surpasses 0.6) of CG dinucleotide bases. They are often associated with the transcription start sites of genes and are also found in gene bodies and intergenic regions. The DNA methylation status of these regions regulates genomic structures and gene transcription.


Proteins that specifically recognize modified DNA, RNA or proteins via special protein domains.

Long non-coding RNAs

Transcripts, longer than 200 nucleotides, that resemble protein-coding mRNAs in that they are capped, spliced and polyadenylated RNA polymerase II transcripts, but they lack a protein-coding open reading frame. They can act in cis or in trans to sequester (decoy) or recruit (guide) regulators from their targets or assemble large complexes (scaffold).

Competing endogenous RNAs

(ceRNAs). Long non-coding RNAs that regulate other RNA transcripts by competing for shared microRNAs.

Enhancer RNAs

(eRNAs). Long non-coding RNAs that are transcribed from active enhancer elements.

Circular RNAs

(circRNAs). Long non-coding RNAs that form a covalently closed RNA loop with the 3΄ and 5΄ ends joined together, acting as sponges for microRNAs.


Enzymes that add specific modifications to DNA, RNA or proteins.


Enzymes that remove specific modifications from DNA, RNA or proteins.

Primary response genes

(PRGs). Genes that are rapidly induced by lipopolysaccharide simply by post-translational activation of transcription factors and are mostly independent of chromatin remodelling.

Secondary response genes

(SRGs). Genes whose induction by lipopolysaccharide requires newly synthesized proteins during the primary response and depend on chromatin remodelling.

RNA Pol II transcriptional elongation

During gene transcription, after RNA polymerase II (RNA Pol II) binds the promoter and initiates DNA transcription, a transcription elongation factor such as P-TEFb mediates productive elongation to generate full-length properly processed mRNAs.

COMPASS complex

A conserved protein complex that catalyses methylation of histone H3. Originally identified as the first H3K4 methylase in yeast, in which it is associated with a trithorax-related SET domain protein. In mammals, it contains a catalytic subunit (SETD1A or SETD1B) and other members such as ASH2L and KMT2A.

Histone code

Post-translational modifications of histone proteins that regulate the accessibility of chromatin-bound DNA to the general transcription machinery to provide an instructive code for cell-specific and tissue-specific gene expression.


A genomic region containing a group of putative enhancers in close genomic proximity with unusually high levels of transcription factor and mediator co-activator binding that enhances gene transcription.

M1 and M2 macrophages

‘M1’ and ‘M2’ are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when classically activated with interferon-γ (IFNγ) and lipopolysaccharide (LPS)) or anti-inflammatory (when alternatively activated with IL-4 or IL-10), respectively. However, in vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regard to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

Warburg effect

The phenomenon in which inflammatory and cancer cells demonstrate a shift in energy metabolism away from oxidative phosphorylation (which is dominant in resting cells) towards aerobic glycolysis, thereby making them able to more rapidly provide ATP and metabolic intermediates for the biosynthesis of immune and inflammatory proteins.

Tricarboxylic acid cycle

(TCA cycle). Also known as the citric acid cycle or Krebs cycle. This cycle is a series of enzymatic reactions used in aerobic metabolism to release energy through the oxidation of acetyl-CoA to yield ATP and carbon dioxide.


A second infection superimposed on an earlier one, especially by a different kind of pathogen.

SET domain

Suvar3–9, enhancer-of-zeste, trithorax domain. An evolutionarily conserved sequence motif that was initially identified in Drosophila melanogaster. It is present in many histone methyltransferases and is required for methylation of histones and non-histone targets.

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Zhang, Q., Cao, X. Epigenetic regulation of the innate immune response to infection. Nat Rev Immunol 19, 417–432 (2019). https://doi.org/10.1038/s41577-019-0151-6

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