Abstract

Chlamydia are Gram-negative, obligate intracellular bacterial pathogens responsible for a broad spectrum of human and animal diseases. In humans, Chlamydia trachomatis is the most prevalent bacterial sexually transmitted infection worldwide and is the causative agent of trachoma (infectious blindness) in disadvantaged populations. Over the course of its developmental cycle, Chlamydia extensively remodels its intracellular niche and parasitises the host cell for nutrients, with substantial resulting changes to the host cell transcriptome and proteome. However, little information is available on the impact of chlamydial infection on the host cell epigenome and global gene regulation. Regions of open eukaryotic chromatin correspond to nucleosome-depleted regions, which in turn are associated with regulatory functions and transcription factor binding. We applied formaldehyde-assisted isolation of regulatory elements enrichment followed by sequencing (FAIRE-Seq) to generate temporal chromatin maps of C. trachomatis-infected human epithelial cells in vitro over the chlamydial developmental cycle. We detected both conserved and distinct temporal changes to genome-wide chromatin accessibility associated with C. trachomatis infection. The observed differentially accessible chromatin regions include temporally-enriched sets of transcription factors, which may help shape the host cell response to infection. These regions and motifs were linked to genomic features and genes associated with immune responses, re-direction of host cell nutrients, intracellular signalling, cell–cell adhesion, extracellular matrix, metabolism and apoptosis. This work provides another perspective to the complex response to chlamydial infection, and will inform further studies of transcriptional regulation and the epigenome in Chlamydia-infected human cells and tissues.

Highlights

  • Members of the genus Chlamydia are Gram-negative, obligate intracellular bacterial pathogens responsible for a broad spectrum of human and animal diseases [1]

  • We identify both conserved and time-specific infection-responsive changes to a variety of features and regulatory elements over the course of the chlamydial developmental cycle that may shape the host cell response to infection, including promotors, enhancers, and transcription factor motifs

  • We find altered chromatin accessibility in several gene regions, ontologies and transcription factors (TF) motifs associated with ECM moieties, cadherins and their interconnected regulatory pathways, and Smad signalling

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Summary

Introduction

Members of the genus Chlamydia are Gram-negative, obligate intracellular bacterial pathogens responsible for a broad spectrum of human and animal diseases [1]. Bacterial effector proteins targeting the nucleus (nucleomodulins) can influence cell physiology and directly interfere with transcriptional machinery including chromatin remodelling, DNA replication and repair [12]. Host cell epigenetic-mediated transcriptional regulatory changes, including histone modifications, DNA methylation, chromatin accessibility, RNA splicing, and non-coding RNA expression [13,14,15] may be arbitrated by bacterial proteins and effectors. Consistent with host cell interactions with other bacterial pathogens, C. trachomatis infection alters host cell transcription over the course of its developmental cycle [16] and may modulate the host cell epigenome. The ultimate gene targets of NUE activity or the affected host transcriptional networks are uncharacterised, as is the influence of chlamydial infection on the host cell epigenome in general.

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