Abstract
Various pathogens systematically reprogram gene expression in macrophages, but the underlying mechanisms are largely unknown. We investigated whether the enteropathogen Yersinia enterocolitica alters chromatin states to reprogram gene expression in primary human macrophages. Genome-wide chromatin immunoprecipitation (ChIP) seq analyses showed that pathogen-associated molecular patterns (PAMPs) induced up- or down-regulation of histone modifications (HMod) at approximately 14500 loci in promoters and enhancers. Effectors of Y. enterocolitica reorganized about half of these dynamic HMod, with the effector YopP being responsible for about half of these modulatory activities. The reorganized HMod were associated with genes involved in immune response and metabolism. Remarkably, the altered HMod also associated with 61% of all 534 known Rho GTPase pathway genes, revealing a new level in Rho GTPase regulation and a new aspect of bacterial pathogenicity. Changes in HMod were associated to varying degrees with corresponding gene expression, e. g. depending on chromatin localization and cooperation of the HMod. In summary, infection with Y. enterocolitica remodels HMod in human macrophages to modulate key gene expression programs of the innate immune response.
Highlights
Macrophages play an essential role in the response to bacterial infection
We analyzed genome-wide epigenetic histone modifications and associated gene expression changes in primary human macrophages infected with enteropathogenic Yersinia enterocolitica
We demonstrate that Yersinia virulence factors extensively modulate histone modifications and associated gene expression triggered by the pathogen-associated molecular patterns (PAMPs) of the bacteria
Summary
Macrophages play an essential role in the response to bacterial infection. They sense pathogenassociated molecular patterns (PAMPs) like lipopolysaccharide (LPS), nucleic acids or flagellin through Toll-like, RIG-I-like or NOD-like pattern recognition receptors (PRRs), respectively [1,2]. While PRRs recognize a wide variety of PAMPs, their downstream signaling often converges on mitogen activated protein kinase- (MAPK), nuclear factor κB- (NF-κB) and type I interferon (IFN) signal pathways [2,5] These pathways include activation of transcription factors that control expression of genes for cytokines, chemokines, and inflammasome components, as well as genes for metabolism, cytoskeleton regulation, and transcriptional regulation [2,6,7,8,9]. The inflammatory gene expression programs in macrophages form an intricate network that is characterized by crosstalk and feedback loops [10,12] Because of their central role in immune defense, numerous pathogenic bacteria have developed mechanisms to suppress or modulate macrophage gene expression [13]
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