Publication Date
12-9-2025
Journal
JCI Insight
DOI
10.1172/jci.insight.193686
PMID
41364527
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, monocytes and macrophages of naïve and Mycobacterium avium infected mice. Interferon 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 two 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.
Keywords
Epigenetics, Hematology, Immunology, Innate immunity, Memory
Published Open-Access
yes
Recommended Citation
Tran, Brandon T; Luna, Pamela N; Cao, Ruoqiong; et al., "Rare Epigenetic Alterations Are Conserved Across Hematopoietic Differentiation Stages After Mycobacterial Infection" (2025). Faculty, Staff and Students Publications. 6307.
https://digitalcommons.library.tmc.edu/baylor_docs/6307
Graphical Abstract