Comparative multi-omics of the macrophage response to infection with Mycobacterium tuberculosis complex bacteria reveals pathogen-driven epigenomic reprogramming

Thomas J Hall
Morgane Mitermite
John F O’Grady
John A Browne
Gillian P McHugo
Emily L Clark
Mazdak Salavati
Stephen V Gordon
David E MacHugh author has email address

Animal Genomics Laboratory, UCD School of Agriculture and Food Science, UCD College of Health and Agricultural Sciences, University College Dublin, Dublin, Ireland
UCD School of Veterinary Medicine, UCD College of Health and Agricultural Sciences, University College Dublin, Dublin, Ireland
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom
Dairy Research and Innovation Centre, SRUC South and West Faculty, Dumfries, United Kingdom
UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
UCD One Health Centre, University College Dublin, Dublin, Ireland

https://doi.org/10.7554/eLife.111920.1

Open access
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Figures and data

Experimental and computational workflow.

Laboratory bovine alveolar macrophage (bAM) challenge, data generation, and data integration steps are shown.

Gene expression and differentially expressed genes (DEGs) in bovine alveolar macrophages (bAM) challenged with Mycobacterium bovis (MBO), M. tuberculosis (MTU), M. bovis BCG (BCG), gamma-irradiated (killed) M. bovis (IRR), and a non-challenged control (CON).

a PCA summary of gene expression data across the five challenge groups. b Numbers of DEGs (FDR-P_adj. < 0.05; |log₂FC| > 0| for all 10 possible contrasts. c UpSet plot showing the intersection of shared DEGs across the four primary bAM challenges (MBO/CON, MTU/CON, BCG/CON, and IRR/CON). d Binned jitter plot of log₂FC values for the 419 significant DEGs across the four primary bAM challenges (MBO/CON, MTU/CON, BCG/CON, and IRR/CON).

Volcano plots showing statistically significant (FDR-P_adj. < 0.05) differentially expressed genes (DEGs) for the four primary MTBC bAM challenges.

Orange data points represent genes with |log₂FC values| < 1, and red data points denote genes with |log₂FC values| ≥ 1. The top ten genes ranked by −log₁₀ FDR-P_adj. are also shown for each contrast. a Mycobacterium bovis vs. control (MBO/CON). b M. tuberculosis vs. control (MTU/CON). c M. bovis BCG vs. control (BCG/CON). d gamma-irradiated (killed) M. bovis vs. control (IRR/CON).

Circular plots of bAM challenge genome-wide peak distributions for ChIP-seq histone modification (H3K4me3, H3K4me3, H3K27ac, and H3K27me3) and ATAC-seq data.

The bottom-right radial key shows the concentric circular plots for each epigenomic data type. a Mycobacterium bovis (MBO). b M. tuberculosis (MTU). c M. bovis BCG (BCG). d Gamma-irradiated (killed) M. bovis (IRR). e Control non-challenged (CON).

Volcano plots showing ChIP-seq H3K27ac differential affinity binding site (DABS) results for the four primary MTBC bAM challenges.

The horizontal dotted line indicates the statistical significance threshold (FDR-P_adj. < 0.05). Orange and red data points indicate significant DAB results (MTBC challenge vs. CON) with |log₂FC values| < 1 and ≥ 1, respectively. a Mycobacterium bovis vs. control (MBO/CON). b M. tuberculosis vs. control (MTU/CON). c M. bovis BCG vs. control (BCG/CON). d gamma-irradiated (killed) M. bovis vs. control (IRR/CON).

Gene expression results for genes involved in the processes of histone methylation and acetylation.

Differentially expressed genes that are statistically significant (FDR-P_adj. < 0.05) are indicated with an asterisk (*), and the heatmap shows log₂FC values. The four primary bAM challenge contrasts are shown: Mycobacterium bovis vs control (MBO); M. tuberculosis vs control (MTU); M. bovis BCG vs control (BCG); and gamma-irradiated (killed) M. bovis vs control (IRR).

Statistically significant differential chromatin modifications for the four MTBC challenge groups versus the control non-challenged group.

Network representations of the regulatory relationships among genes, histone modifications, and chromatin accessibility for the four primary MTBC bAM challenges.

Each circular node in each network corresponds to a gene observed to be co-located with a differential histone modification or chromatin accessibility difference (represented as square anchor hub nodes). The circular node colour shows if a gene was differentially expressed (upregulated: red; downregulated: blue; and yellow: not differentially expressed). The lines (edges) between nodes show if a histone modification difference/chromatin accessibility change was larger (determined by log₂FC for peak sizes) in the challenged bAM (red) or in the control non-challenged bAM (blue). Circular gene node size is determined by the number of connecting edges (degree). The numbers shown in each of the four keys represent the numbers of nodes (N) and interactions (I). a M. bovis vs control (MBO/CON). b M. tuberculosis vs control (MTU/CON). c M. bovis BCG vs control (BCG/CON). d gamma-irradiated (killed) M. bovis vs control (IRR/CON).

Integration of the MBO/CON overlap gene subset (928 genes) with a Holstein-Friesian M. bovis infection susceptibility trait GWAS dataset.

a Circular Manhattan plot showing GWAS results before integration of the MBO/CON overlap gene subset. b Circular Manhattan plot showing GWAS results after integration of the MBO/CON overlap gene subset with the gwinteR tool. Large blue and green data points indicate binned statistically significant SNP clusters (FDR-P_adj. < 0.10) prior to, and post-integration, respectively.

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