Chromatin accessibility dynamics ofChlamydia-infected epithelial cells

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 genomewide chromatin accessibility associated with C. trachomatis infection. The observed differentially accessible chromatin regions, including several Clusters of Open Regulatory Elements (COREs) and temporally-enriched sets of transcription factors, 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 signaling, 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

Early Transcriptional Landscapes of Chlamydia trachomatis-Infected Epithelial Cells at Single Cell Resolution

“…As a result, many infection and disease processes at the cellular and tissue level remain largely unknown or poorly characterized in vivo . Gene expression profiling of Chlamydia -infected cells by microarray (Porcella et al, 2015), dual RNA-Seq (Humphrys et al, 2013; Marsh et al, 2018), or other genome-scale analyses (Hayward et al, 2019) are powerful techniques to help deconvolute these interactions and processes. However, these and similar genome-scale analyses of infected cells have typically been performed on bulk cell populations, i.e., infected cell monolayers in vitro , or selectively sorted/purified subsets of cell populations.…”

“…Clustering, pseudotime and cell state prediction analyses demonstrated that Chlamydia -treated cells at 3 h are readily distinguishable from Chlamydia -treated and mock-infected cells at 6 and 12 h. Curiously, cells at 6 and 12 h clustered together and could not be further deconvoluted from each other, possibly showing that host cell transcription at these times is broadly similar. A recent FAIRE-Seq analysis of Chlamydia -infected epithelial cells, examining patterns of host cell chromatin accessibility over the developmental cycle (Hayward et al, 2019), found that 12 h post-infection was relatively quiescent in terms of host cell transcriptional activity. This finding is reflected by our scRNA-Seq analyses here and may be extended to 6 h post-infection.…”

Early transcriptional landscapes ofChlamydia trachomatis-infected epithelial cells at single cell resolution

“…Curiously, cells at 6 and 12 hours clustered together and could not be further deconvoluted from each other, showing that host cell transcription at these times is broadly similar. A recent FAIRE-Seq analysis of Chlamydia-infected epithelial cells, examining patterns of host cell chromatin accessibility over the developmental cycle[54], found that 12 hours post infection was relatively quiescent in terms of host cell transcriptional activity. This finding is reflected by our scRNA-Seq analyses here and may be extended to 6 hours post-infection.…”