Rare epigenetic alterations are conserved across hematopoietic differentiation stages after mycobacterial infection
Brandon T. Tran, Pamela N. Luna, Ruoqiong Cao, Duy T. Le, Apoorva Thatavarty, Laure Maneix, Bailee N. Kain, Scott Koh, Andre Catic, Katherine Y. King
Brandon T. Tran, Pamela N. Luna, Ruoqiong Cao, Duy T. Le, Apoorva Thatavarty, Laure Maneix, Bailee N. Kain, Scott Koh, Andre Catic, Katherine Y. King
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Research Article Hematology Immunology

Rare epigenetic alterations are conserved across hematopoietic differentiation stages after mycobacterial infection

Abstract

Infection leads to durable cell-autonomous changes in hematopoietic stem and progenitor cells (HSPCs), resulting in production of innate immune cells with heightened immunity. The mechanisms underlying this phenomenon, termed central trained immunity, remain poorly understood. We hypothesized that infection induces histone modifications leading to changes in chromatin accessibility that are conserved during differentiation from HSPCs to myeloid progenitors and monocytes. We conducted genome-wide surveillance of histone marks H3K27ac and H3K4me3 and chromatin accessibility in hematopoietic stem cells, multipotent progenitor 3, granulocyte-monocyte progenitors, and monocytes and macrophages of naive and Mycobacterium avium–infected mice. IFN signaling pathways and related transcription factor binding motifs including IRFs, NF-κB, and CEBP showed increased activating histone marks and chromatin accessibility across cell types. However, histone marks and increased chromatin accessibility were conserved at only a few loci, notably Irf1 and Gbp6. Knock out of IRF1 disrupted enhanced mitochondrial respiration and bacterial killing in human monocyte cell lines, while GBP6-KO monocyte cell lines showed dysregulated mitochondrial respiration. In summary, this study identifies IRF1 and GBP6 as 2 key loci at which infection-induced systemic inflammation leads to epigenetic changes that are conserved from HSPCs to downstream monocytes, providing a mechanistic avenue for central trained immunity.

Authors

Brandon T. Tran, Pamela N. Luna, Ruoqiong Cao, Duy T. Le, Apoorva Thatavarty, Laure Maneix, Bailee N. Kain, Scott Koh, Andre Catic, Katherine Y. King

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Figure 1

Mycobacterium avium infection promotes HPSC central trained immunity with enhanced macrophage immune and metabolic function.

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Mycobacterium avium infection promotes HPSC central trained immunity wi...
(A) Experimental design for generating bone marrow–derived macrophages (BMDMs) from hematopoietic stem and progenitor cells (HSPCs). Cells were sorted from pooled mouse bone marrow samples (n = 5–7 per group), cKit-enriched, and sorted for lineage– cells. BMDMs generated from sorted cells were counted and seeded for respective assays after culture. (B) Seahorse Mitostress test assay in M. avium–trained BMDMs (red) and naive/untrained BMDMs (blue). Experiment was repeated twice. (C and D) Calculated maximum oxygen consumption rate (C) and proton leak (D) of M. avium–trained and naive BMDMs. (E and F) TNF-α (E) and IL-6 (F) secreted by M. avium–trained and naive BMDMs. Cytokine release assay performed once. (G) Experimental schematic for trained immunity chimeric transplant and challenge model. In total, 200,000 CD45.2 cKit+ cells from naive or M. avium–trained mice were transplanted with 200,000 CD45.1 rescue marrow into lethally irradiated CD45.1 recipients, which were challenged with M. avium 12 weeks after transplant. (H) Splenic M. avium colony forming units counts from M. avium–trained and naive challenged transplant recipients. n = 4–6 per experiment, representative findings from 2 independent experiments. Mean ± SEM shown per experiment. For statistical analysis (C, D, and H), 2-tailed Student’s unpaired t test. E and F used ordinary 1-way ANOVA. *P < 0.05, **P < 0.01.