Rewiring the bone marrow: Evolution and the transcriptional architecture of trained immunity
- Committee on Immunology, University of Chicago, United States
- Medical Scientist Training Program, University of Chicago, United States
- Section of Genetic Medicine, Department of Medicine, University of Chicago, United States
- Department of Human Genetics, University of Chicago, United States
- Committee on Genetics, Genomics, and Systems Biology, University of Chicago, United States
- Chan Zuckerberg Biohub Chicago Investigator, United States
Figures
Figure 1
Heatmap of human and mouse studies with transcription factors (TFs) colored according to their ranked motif or expression (Bacillus Calmette–Guérin [BCG] mouse) enrichment within hematopoietic stem and progenitor cells (HSPCs) 1 or more months following training with the indicated stimulus.
Each column represents a different study. Studies are grouped by stimulus type (top gray boxes). Species (mouse or human) is indicated on the bottom x-axis. White squares indicate no significant enrichment (NE).
Figure 2
Conservation scores (shet) for cytokines (green) and transcription factors (TFs) (purple) implicated across mouse and human studies of hematopoietic reprogramming, compared to all other genes (gray).
The figure shows posterior distributions of shet for individual genes, ordered by mean. Lines represent 95% credible intervals, with labeled genes represented by thick black lines. Colors represent the selection regimes. The inset panel summarizes shet values for TFs involved in hematopoietic reprogramming (HR-TFs), comparing them to all other TFs and to the rest of the genome.
Tables
Table 1
Cytokine-induced hematopoietic reprogramming.
The table includes stimuli of hematopoietic reprogramming from studies for which cytokines were directly investigated. The phenotype-defining cytokine is bolded. Rows are colored according to cytokine (red—IL1β, yellow—IL6 ± IFN, blue—IFN in the absence of IL6). Stimuli that induce similar cytokine repertoires also produce similar reprogramming effects.
| Stimulus | Species studied | Type | Key cytokines induced | Persistent reprogramming outcome | References |
|---|---|---|---|---|---|
| β-Glucan | Mice | Infectious mimic (PRR agonist) and inflammasome activator | IL-1β, G-CSF | Inherent LT-HSC myeloid bias; trained EM response to chemotherapy | Mitroulis et al., 2018 |
| LIP | Mice | Sterile inflammation | IL-1β, G-CSF | Inherent LT-HSC myeloid bias; trained EM response to LPS; primed monocyte and neutrophil TNFα/IL-6 secretion upon LPS challenge | Li et al., 2022 |
| BCG vaccination | Mice | Live attenuated infection | IFN-γ | Increased macrophage antimicrobial activity; IFN-γ dependent | Kaufmann et al., 2018 |
| COVID-19 infection | Human | Viral infection | IL-6 | Lasting monocyte chromatin remodeling and priming; persistent GMP expansion; reversed by IL-6 blockade | Cheong et al., 2023 |
| Western diet | Mice | Metabolic trigger | IL-6, IFN-γ, IL-1β, G-CSF, GM-CSF | Lasting monocyte priming; GMP chromatin remodeling, differential gene expression, monocyte skewing | Christ et al., 2018 |
Table 2
Transcription factors (TFs) implicated in hematopoietic reprogramming fall into four groups.
These range from TFs that are activated and bind chromatin in specific contexts (such as emergency myelopoiesis [EM] for CEBPB) to those that engage in widespread binding and play roles in dictating the global chromatin landscape (stripe factors). Check marks on the right indicate TF involvement within each study.
| TF group | TF function specificity | Key members | Role in hematopoietic reprogramming | Models/Stimuli with evidence of TF group involvement | |||||
|---|---|---|---|---|---|---|---|---|---|
| Mouse | Human | ||||||||
| β-Glucan | BCG | LPS | Western diet | BCG | COVID | ||||
| Lineage | + | C/EBP (β, α, ε, δ) | Required for cytokine-induced EM; downstream of G-CSF through STAT3 | ✓ | ✓ | ✓ | ✓ | ||
| Cytokine responsive | + + | STAT1, STAT3, STAT5 | Mediates cytokine signaling (IL6, IFNs, G-CSF) | ✓ | ✓ | ✓ | ✓ | ||
| Ubiquitous pioneer | + + + | FOS/JUN (AP-1) | Induced in many stimuli; drive enhancer formation and chromatin access | ✓ | ✓ | ✓ | ✓ | ||
| Universal stripe | + + + | KLFs, SPs, EGRs, ZNFs | Enables through co-binding other TFs shaping epigenetic landscape | ✓ | ✓ | ✓ | |||
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Rewiring the bone marrow: Evolution and the transcriptional architecture of trained immunity
eLife 14:e107551.
https://doi.org/10.7554/eLife.107551
