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Epigenetic profiling across hematopoietic stages identifies genomic loci with conserved chromatin alterations after 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 immune function. The mechanisms underlying this phenomenon, termed central trained immunity, remain poorly understood. We hypothesized that infection induces histone modifications in chromatin, leading to changes in chromatin accessibility that are passed down from HSPCs to myeloid progenitors, monocytes and macrophages. To test this hypothesis, we conducted genome-wide surveillance of activating histone marks H3K27Ac and H3K4me3 and transposon accessibility of chromatin in hematopoietic stem cells, multipotent progenitor 3, granulocyte-monocyte progenitors, monocytes and macrophages of naïve versus Mycobacterium avium infected mice. While activating histone marks and chromatin accessibility were increased broadly in biological responses to interferon and cytokine signaling. Consistent with this finding, transcription factor binding motifs related to interferon signaling, including IRFs, NF-kB, and CEBP, were highly enriched across cell types. However, activating histone marks and increased chromatin accessibility were commonly induced at only a few loci including Irf1 and Gbp6 across multiple stages of differentiation. In summary, processing of inflammatory signaling upon systemic infection leads to epigenetic changes in HSPCs, and these changes are conserved at a small number of genetic loci in downstream monocytes.

ORGANISM(S): Mus musculus

PROVIDER: GSE280820 | GEO | 2025/12/02

REPOSITORIES: GEO

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Project description:The establishment of latency is an essential step for the life-long persistent infection and pathogenesis of KaposiM-bM-^@M-^Ys sarcoma-associated herpesvirus (KSHV). While the KSHV genome is chromatin-free in the virions, the viral DNA in latently infected cells has a chromatin structure that is characterized by a specific pattern of activating and repressive histone modifications that ultimately promote latent gene expression while suppressing lytic gene expression. To investigate the molecular events involved in the establishment of the latent chromatin structure during the pre-latency phase of KSHV infection, we performed a comprehensive epigenetic study to analyze the recruitment of chromatin regulatory factors onto the KSHV genome at various time-points following de novo infection of SLK and TIME cells. This showed that the KSHV genome undergoes a biphasic chromatinization following de novo infection. Initially, a transcriptionally active chromatin (euchromatin), characterized by high levels of the H3K4me3 and acetylated H3K27 (H3K27ac) activating histone marks, was deposited on the viral episome and was accompanied by the temporary induction of a limited number of lytic genes. Interestingly, transient expression of the RTA protein facilitated the increases of H3K4me3 and H3K27ac occupancy on the KSHV episome during de novo infection. Between 24-72 hours post-infection, as the levels of these activating histone marks declined on the KSHV genome, the levels of the repressive H3K27me3 and H2AK119ub histone marks increased concomitantly with the decline of lytic gene expression. Importantly, this transition to heterochromatin was dependent on both the Polycomb Repressive Complex 2 and 1. In contrast, upon infection of human gingiva-derived epithelial cells, the KSHV genome underwent a continuously transcription-active euchromatinization, resulting in efficient lytic gene expression. Our data demonstrate that the KSHV genome undergoes a temporally ordered biphasic euchromatin-to-heterochromatin transition in endothelial cells, leading to latent infection, whereas KSHV preferentially adopts a transcriptionally active euchromatin in oral epithelial cells, resulting in lytic gene expression. Our results suggest that the differential epigenetic modification of the KSHV genome in distinct cell types is a potential determining factor for latent infection vs. lytic replication of KSHV. Please see above. 16 hybridizations: ChIP and Input DNA

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Epigenetic profiling across hematopoietic stages identifies genomic loci with conserved chromatin alterations after infection

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