African swine fever virus reshapes host genome architecture within hours of infection

African swine fever is among the most devastating diseases of domestic pigs, and the virus that causes it remains one of the most formidable pathogens in modern agriculture. A new study published in Cellular and Molecular Life Sciences now reveals that the opening moves of this infection are fought not only in the cytoplasm, where the virus replicates, but deep inside the host cell nucleus. An international team of researchers led by Gang Cao and Ke Xiao has shown that African swine fever virus (ASFV) dramatically reorganizes the three-dimensional architecture of host chromatin during the earliest hours of infection, a process that appears to help the pathogen suppress the antiviral defenses of its preferred target cell, the macrophage.

ASFV belongs to the nucleocytoplasmic large DNA viruses, a group of complex viruses whose genomes encode many of their own replication machinery. Although the virus assembles and replicates in cytoplasmic factories, its entry into a macrophage sets off a cascade of events that reaches into the nucleus. Previous work had suggested that ASFV can modulate host gene expression epigenetically, but the scale and dynamics of the nuclear changes during early infection had never been systematically mapped. The new study addresses that gap by tracking the infection at 2, 4, and 6 hours post-infection, a window in which the virus establishes itself before progeny virions begin to spread.

To capture this pivotal phase, the researchers deployed an unusually comprehensive multi-omics strategy. Time-course RNA sequencing charted the host transcriptome as it changed hour by hour. CUT&Tag profiling measured where RNA polymerase II, the enzyme that transcribes protein-coding genes, was sitting across the genome. Immunoprecipitation followed by mass spectrometry identified the proteins that associate with the polymerase during infection. Finally, Hi-C, a method that captures the physical contacts between distant stretches of chromatin, revealed how the genome folds in three-dimensional space. Crucially, the team ran this entire pipeline using both a virulent ASFV strain and its live-attenuated derivative, allowing them to distinguish changes caused by the virus in general from those attributable to specific virulence factors.

The most striking finding concerns the global organization of the genome. In healthy cells, chromatin is partitioned into compartments of active euchromatin and silent heterochromatin, and further subdivided into topologically associating domains, or TADs, which are self-contacting genomic neighborhoods that help regulate which genes talk to which regulatory elements. The study found that early ASFV infection significantly increased heterochromatinization across the host genome, shifted the positions of TAD boundaries, and altered both the intensity of chromatin interactions and the spatial distances between interacting genomic regions. In other words, within hours of the virus entering the cell, the host genome was physically refolded.

One of the most intriguing observations is that viral DNA itself appears to participate in this reorganization. The Hi-C data revealed interactions between viral genomes and host chromatin, suggesting that incoming ASFV DNA does not simply float in the nucleus as an inert passenger. Instead, it seems to make physical contact with host chromosomes, raising the possibility that the virus actively recruits host genomic regions to viral replication compartments or sequesters immune genes into repressive nuclear environments. The authors suggest that this chromatin reorganization may contribute to ASFV immune evasion, though the precise mechanisms linking physical genome folding to immune suppression remain to be worked out.

The transcriptional consequences of this remodeling were equally revealing. The host antiviral transcriptional program, the set of interferon-stimulated genes and inflammatory pathways that normally swing into action when a macrophage detects a pathogen, turned out to be indistinguishable between cells infected with the virulent strain and cells infected with the attenuated virus. This was a surprise, because the attenuated strain lacks MGF-encoded factors, a family of viral genes long associated with virulence and immune modulation. The result demonstrates that the earliest wave of innate immune activation is independent of these virulence determinants, implying that whatever the MGF proteins do to tip the balance toward lethal disease must happen later, or through mechanisms other than silencing the initial antiviral transcriptional response.

RNA polymerase II itself became a focal point of the analysis. The researchers found that the total protein levels of the polymerase did not change appreciably during early infection, yet its behavior was profoundly altered. Its genomic occupancy was redistributed across the genome, and its interactome, the network of proteins it physically associates with, was remodeled. Core polymerase subunits and components of the Mediator complex, a large coactivator that bridges transcription factors to the polymerase, became enriched in the polymerase-associated fraction. In contrast, sequence-specific transcription factors, the proteins that normally direct the polymerase to particular genes in response to signals, were depleted from that fraction.

This shift in the polymerase’s social circle is mechanistically significant. A polymerase that is increasingly bound to Mediator and core subunits but less associated with gene-specific transcription factors suggests a reprogramming of transcriptional control away from signal-responsive gene activation and toward a more basal or virally steered mode. Combined with the increased heterochromatinization and the repositioning of TAD boundaries, the picture that emerges is one of coordinated change: the physical folding of the genome, the distribution of the transcription machinery, and the resulting transcriptome are all being reshaped together during the first six hours of infection.

The implications extend beyond basic virology. African swine fever continues to inflict substantial economic losses on the global swine industry, and the absence of a widely available safe and effective vaccine has made understanding the virus’s evasion strategies a research priority. By showing that ASFV manipulates host chromatin architecture so early and so extensively, the study opens a new dimension for antiviral intervention. If specific host factors mediate the observed heterochromatinization or the redistribution of polymerase occupancy, those factors could become drug targets. Similarly, the finding that early innate immune activation proceeds normally even without MGF-encoded virulence factors suggests that the critical battle between host defense and viral evasion is fought on a chromatin landscape, not merely at the level of individual signaling pathways.

The work also adds ASFV to a growing list of viruses known to touch the three-dimensional genome, but with a distinctive twist. Because ASFV is a cytoplasmic replicator, its nuclear influence must be exerted through delivered proteins, RNAs, or the viral DNA itself, rather than through a nuclear replication cycle. Disentangling which viral components drive the chromatin remodeling, and determining whether blocking that remodeling restores full antiviral gene expression, are the natural next questions. For now, the study provides the most systematic view yet of how a lethal agricultural pathogen rewrites the physical grammar of the host genome in its opening hours, and it suggests that the nucleus, long viewed as a bystander in ASFV infection, is in fact an active battlefield.

Subject of Research: Chromatin architecture remodeling in host cells during early African swine fever virus infection

Article Title: ASFV early infection dynamically remodels host chromatin architecture to evade immune responses

Article References: Xu, Y., Yang, B., Zhu, J., Sunkang, Y., Xing, L., Wang, C., Yang, J., Xu, W., Dai, J., Zhang, J., Cao, G., & Xiao, K. (2026). ASFV early infection dynamically remodels host chromatin architecture to evade immune responses. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06467-9

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06467-9

Keywords: African swine fever virus, ASFV, chromatin architecture, Hi-C, RNA polymerase II, macrophages, immune evasion, topologically associating domains, heterochromatin, innate immunity, virus-host interactions, multi-omics