Modulation of gene expression and epigenetic modifications in human macrophages by Yersinia enterocolitica

Abstract

Pathogenic Yersinia spp. extensively suppress expression of inflammatory genes via injection of virulence plasmid-encoded factors into macrophages. At this point a global analysis of virulence factor regulation of gene expression in primary human macrophages is missing and it is not known whether epigenetic modifications are involved. To address these questions we performed a global gene expression and epigenetic analysis with RNA-seq and ChIP-seq, respectively, in primary human macrophages mock-infected or infected with Y. enterocolitica wild type strain WA314 or virulence plasmid-cured strain WAC. ChIP-seq was performed for histone modifications H3K4me1, H3K4me3, H3K27me3 and H3K27ac to analyse association between Yersinia-induced transcription and alterations of chromatin state at promoters and enhancers. WA314 extensively counteracted WAC/ PAMP-induced gene expression and associated H3K4me3 and H3K27ac histone modifications at promoters and enhancers. Effectors suppressed gene expression and respective histone marks of inflammatory response genes and prevented downregulation of metabolic pathway genes. Furthermore, we revealed that expression and chromatin marks associated with Rho GTPase pathway genes were substantially regulated by Yersinia with 324 (61 %) of 534 genes regulated epigenetically. Transcriptional and epigenetic analysis with YopM and YopP effector mutant strains revealed that YopP was a major regulator of the WA314 effects, but other yet uncharacterised factors were involved as well. Moreover, YopP modulation of histone marks was due to the known YopP inhibitory activity of the MAPK pathway. Overall, we show that the main activity of Yersinia virulence factors is to counteract PAMP-induced effects on gene expression and chromatin modifications in macrophages primarily through the activity of YopP. Major epigenetic and transcriptomic regulation of Rho GTPase pathway genes suggests another level of Rho GTPase targeting by Yersinia to modulate actin cytoskeleton.