The hidden DNA code behind a powerful antiviral response
Cells rely on powerful alarm systems to detect and stop viral infections—but these systems must be kept under tight control to avoid damaging healthy tissue. Researchers from the lab of Moritz Gaidt at the IMP have now identified a new gene regulatory mechanism that keeps immune responses restrained while remaining ready for rapid activation. Combining experimental biology and machine learning, the team discovered a cluster of specific DNA motifs within repetitive DNA that acts as a powerful immune switch capable of strongly amplifying inflammation. Their findings are published now in The EMBO Journal.
A cell’s response to viral infection begins with a decision: when to raise the alarm. One of the cell’s most powerful warning signals is interferon, a molecule that the innate immune system uses to alert neighbouring cells of infection and help halt viral spread. But interferon is a double-edged sword. If triggered at the wrong time or too strongly, it can damage healthy tissue and drive harmful inflammation. Cells therefore walk a fine line—keeping this powerful alarm tightly restrained, yet ready to unleash it within moments of infection.
Central to the balance between rapid antiviral defence and harmful inflammation is MORC3, a protein with a dual function. On one hand, MORC3 helps protect cells by stopping viruses from replicating inside the cell. On the other, it keeps interferon production switched off under normal conditions, preventing unnecessary immune reactions. This combination creates a built-in “insurance mechanism”: when viruses disable MORC3 to aid their own replication, they simultaneously lift the repression on interferon—setting off a strong immune response.
Scientists had known that MORC3 keeps this powerful immune response under control, but they did not understand how a single protein could suppress such a strong alarm so precisely.
To answer this question, researchers in the lab of Moritz Gaidt at the IMP teamed up with visiting scientist Jacob Schreiber and the lab of Alexander Stark. Combining experimental biology with machine learning, the researchers discovered that MORC3 controls interferon by locking down a powerful DNA “switch” that can rapidly unleash inflammation when released. Their findings reveal a new principle of immune regulation: the architecture of DNA itself can create exceptionally powerful gene regulatory switches.
How the accumulation of DNA motifs amplifies immune responses
To figure out how MORC3 controls the switch responsible for interferon production, the researchers zoomed in on the DNA sequence that activates it.
Combining genetic experiments with computational analyses, they began to systematically analyse how this region is organised. “What we found was unexpected,” says Luisa Krumwiede, PhD student in the Gaidt lab and first author of the study. “Instead of a typical regulatory region, we saw the same DNA sequence repeated over and over again.”
These repeated DNA units contained multiple binding motifs—short DNA sequences where the transcription factor PU.1 can dock. Together, the repeats created an unusually large cluster of PU.1 binding sites capable of strongly activating immune genes. The researchers believe this structure likely emerged through an evolutionary copy-and-paste mechanism that progressively expanded the region over time.
In collaboration with visiting scientist Jacob Schreiber at the IMP, the researchers also used machine learning tools to analyse how changes in the repetitive DNA sequence affect the activity of the immune switch. These computational analyses confirmed that the repeated PU.1 motifs are the key features driving the unusually strong immune response.
“What makes this system so remarkable is that the same DNA structure has two opposing functions,” explains Krumwiede. “As long as MORC3 is present, it keeps the switch tightly repressed. But once MORC3 is disrupted by a virus, the large number of PU.1 binding sites allows the system to rapidly trigger an exceptionally strong interferon response. It’s the combination of these two functions that creates the switch.”
The researchers believe this unusual architecture also explains the remarkable precision of the system. Only very few regions in the genome contain such large clusters of repeated binding sites, allowing MORC3 to selectively control interferon rather than broadly affecting other genes.
“These findings reveal a new way in which cells regulate interferon,” says Moritz Gaidt. “Instead of relying on classical signalling cascades, this system uses the repeated structure of DNA itself creating a motif cluster that amplifies the signal.”
The study suggests that such motif clusters within repetitive DNA elements may represent a broader class of regulatory switches in the genome. Because the number of repeats can vary between individuals, they could also contribute to differences in how people respond to viral infections.
The researchers now want to investigate whether similar motif clusters regulate other immune responses and biological processes across the genome.
Original publication
Luisa Krumwiede, David Hollaus, Erika Valeri, Karina Schindler-Schumitsch, Monika A Bazyl, Johanna Schiedlbauer, Nanette N Becht, Markus Jaritz, Bernardo P de Almeida, Siegfried Schloissnig, Dara L Burdette, Jacob Schreiber, Alexander Stark and Moritz M Gaidt# “MORC3 represses a tandem repeat enhancer to regulate interferon”. The EMBO Journal (2026).
#Corresponding author
Further reading
Lab of Moritz Gaidt